Bromodomain inhibitor

ABSTRACT

The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.

RELATED APPLICATION

This application claims priority benefit to U.S. Provisional PatentApplication No. 62/148,098, filed 15 Apr. 2015, which is fullyincorporated herein by reference for all purposes.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

SUMMARY

Provided herein are substituted heterocyclic derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for epigenetic regulation byinhibition of bromodomain-mediated recognition of acetyl lysine regionsof proteins, such as histones. Furthermore, the subject compounds andcompositions are useful for the treatment of cancer, such as NUT midlinecarcinoma, prostate cancer, breast cancer, bladder cancer, lung cancer,melanoma, and the like. The substituted heterocyclic derivativecompounds described herein are based upon pyridone and relatedheterocyclic structures. These pyridone and related heterocyclicstructures are substituted at the 4-position with a fused bicyclic groupsuch as an aryl, a heteroaryl and the like, and on the nitrogen atom ofthe isoquinolinone or related heterocyclic structure with a small alkylgroup, such as a methyl group.

At least one embodiment provides a compound of Formula I, or apharmaceutically acceptable salt thereof, Formula I represented by:

wherein

-   -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X5 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl        or alkoxy;    -   X6 is N or C—R¹⁶, wherein R¹⁶ is hydrogen, halogen, or —W—X,        wherein        -   W is a bond, —O—, —S—, or —NH—, and        -   X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   G represented by:

-   -   wherein,        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form a ring that is optionally            substituted;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or        -   optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, and            R²⁶ is neither hydrogen nor halogen, then R²⁵ and R²⁶ join            to form an optionally substituted ring; provided that the            compound of Formula I is neither    -   4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-methylisoquinolin-1(2H)-one,    -   2-methyl-4-(2-oxoindolin-6-yl)isoquinolin-1(2H)-one,    -   4-methyl-6-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one,    -   nor    -   4-(1′-cyclobutyl-4H-spiro[benzo[d][1,3]dioxine-2,4′-piperidine]-6-yl)-2-methylisoquinolin-1(2H)-one.

At least one embodiment provides a compound of Formula II, or apharmaceutically acceptable salt thereof, wherein Formula II isrepresented by

wherein

-   -   Ring B is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, wherein        -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-,        -   Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b),            —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂,            —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),            —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), in            which            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl;    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein        -   W is a bond, —O—, —S—, or —NH—, and        -   X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   G is described by:

-   -   wherein        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl; and        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or        -   optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, and            R²⁶ is neither hydrogen nor halogen, then R²⁵ and R²⁶ join            to form an optionally substituted ring.

At least one embodiment provides a compound of Formula III, or apharmaceutically acceptable salt thereof,

wherein

-   -   Ring C is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one O, S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, wherein        -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-, and        -   Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b),            —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂,            —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),            —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), in            which            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl;    -   X4 is N or C—R¹⁴, in which R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; and    -   G is described by:

-   -   wherein        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or        -   optionally, when both R²³ and R²⁵ are not hydrogen, and R²⁶            is neither hydrogen nor halogen, then R²⁵ and R²⁶ join to            form an optionally substituted ring; provided that the            compound of Formula III is neither    -   4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one    -   nor    -   4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.

At least one embodiment provides a compound of Formula IV, or apharmaceutically acceptable salt thereof, Formula IV represented by:

wherein

-   -   each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;    -   R¹³ is —Y—Z, in which        -   Y is a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-,        -   Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,            —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),            —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂,            —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl;    -   R¹⁶ is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   G is:

-   -   wherein        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or    -   optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, and R²⁶        is neither hydrogen nor halogen, then R²⁵ and R²⁶ join to form        an optionally substituted ring.

In one embodiment, the compound of Formula IV, or a pharmaceuticallyacceptable salt thereof, is a compound of Formula IVa:

In an embodiment of Formula IVa, R¹³ is —Y—Z, in which Y is s a bond or—CH₂—, and Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), or —SO₂N(R^(a))₂, whereineach R^(a) is independently hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, and R^(b) is alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; R¹⁶ is alkyl, alkynyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and G is as describedabove.

In another embodiment of Formula IVa, R¹³ is —Y—Z, wherein Y is a bondor —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), in which each R^(a) isindependently hydrogen or alkyl, and R^(b) is alkyl; R¹⁶ is alkyl orcycloalkylalkyl; and G is as described above.

At least one embodiment provides a compound of Formula Va:

or a pharmaceutically acceptable salt thereof, wherein

-   -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X5 is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl        or alkoxy; and    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein        -   W is a bond, —O—, —S—, or —NH—, and        -   X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula Vb:

or a pharmaceutically acceptable salt thereof, wherein

-   -   Ring B is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, wherein        -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-, and        -   Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b),            —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂,            —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),            —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b),            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl; and    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein        -   W is a bond, —O—, —S—, or —NH—, and        -   X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula Vc, or apharmaceutically acceptable salt thereof,

wherein

-   -   Ring C is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one O, S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, wherein        -   Y is a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-, and        -   Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,            —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),            —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂,            —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl; and    -   X4 is N or C—R¹⁴, in which R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy.

At least one embodiment provides a compound of Formula Vd, or apharmaceutically acceptable salt thereof,

wherein

-   -   each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;    -   R¹³ is —Y—Z, in which        -   Y is a bond, —CH₂— or —CH(C₁-C₄ alkyl)-, and        -   Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,            —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),            —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂,            —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein            -   each R^(a) is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,                aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or                heteroarylalkyl; and    -   R¹⁶ is from alkyl, alkynyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula Ve:

or a pharmaceutically acceptable salt thereof, wherein

-   -   J is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z, in which        -   Y is a bond, —CH₂—, or —CH(C₁-C₄alkyl)-, and        -   Z is —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,            —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,            —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, in            which            -   each R²¹ is independently alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and                wherein            -   each R²² is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   K is N or C—R¹⁴, in which R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   Q is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy; and    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein        -   W is a bond, —O—, —S—, or —NH—, and        -   X is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl,            heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula VI, or apharmaceutically acceptable salt thereof, in which Formula VI is

wherein

-   -   n is 0 to 4;    -   m is 0 or 1;    -   R^(A) is a halogen, C1-3 alkyl, or C1-3 alkoxy;    -   J is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z, in which        -   Y is a bond, —CH₂—, or —CH(C₁-C₄alkyl)-, and        -   Z is —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,            —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,            —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹,            wherein            -   each R²¹ is independently alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and            -   each R²² is independently hydrogen, alkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, heterocyclyl,                heterocyclylalkyl, heteroaryl, or heteroarylalkyl.    -   K is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   Q is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy; and    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a        bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl,        cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        or heteroarylalkyl.

At least one embodiment provides a pharmaceutical composition comprisinga compound of Formula I, or a pharmaceutically acceptable salt thereof.At least one embodiment provides a pharmaceutical composition comprisinga compound of Formula II, or a pharmaceutically acceptable salt thereof.At least one embodiment provides a pharmaceutical composition comprisinga compound of Formula III, or a pharmaceutically acceptable saltthereof. At least one embodiment provides a pharmaceutical compositioncomprising a compound of Formula IV, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a pharmaceuticalcomposition comprising a compound of Formula IVa, or a pharmaceuticallyacceptable salt thereof. At least one embodiment provides apharmaceutical composition comprising a compound of Formula Va, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a pharmaceutical composition comprising a compound of FormulaVb, or a pharmaceutically acceptable salt thereof. At least oneembodiment provides a pharmaceutical composition comprising a compoundof Formula Vc, or a pharmaceutically acceptable salt thereof. At leastone embodiment provides a pharmaceutical composition comprising acompound of Formula Vd, or a pharmaceutically acceptable salt thereof.At least one embodiment provides a pharmaceutical composition comprisinga compound of Formula Ve, or a pharmaceutically acceptable salt thereof.At least one embodiment provides a pharmaceutical composition comprisinga compound of Formula VI, or a pharmaceutically acceptable salt thereof.

At least one embodiment provides a method of treating a cancer patientin need thereof, comprising administering to the patient apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a method of treating cancer in a patient in need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula II, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a method of treating acancer patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound of Formula III, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a method of treating a cancer patient in need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula IV, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a method of treating acancer patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound of Formula IVa, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a method of treating a cancer patient in need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula Va, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a method of treating acancer patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound of Formula Vb, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a method of treating a cancer patient in need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula Vc, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a method of treating acancer patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound of Formula Vd, or apharmaceutically acceptable salt thereof. At least one embodimentprovides a method of treating a cancer patient in need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula Ve, or a pharmaceutically acceptablesalt thereof. At least one embodiment provides a method of treating acancer patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound of Formula VI, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention, which is defined solely by the claims.

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention, but are not to providedefinitions of terms inconsistent with those presented herein. Thesepublications are provided solely for their disclosure prior to thefiling date of the present application. Nothing in this regard should beconstrued as an admission that the inventors are not entitled toantedate such disclosure by virtue of prior invention or for any otherreason. All statements as to the date or representation as to thecontents of these documents is based on information available to theapplicants and do not constitute any admission as to the correctness ofthe dates or contents of these documents.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. Throughout this specification, unless otherwise indicated,“comprise,” “comprises” and “comprising” are used inclusively ratherthan exclusively, so that a stated integer or group of integers mayinclude one or more other non-stated integers or groups of integers. Theterm “or” is inclusive unless modified, for example, by “either.” Otherthan in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about.”

Headings are provided for convenience only and are not to be construedto limit the invention in any way. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning asthose commonly understood to one of ordinary skill in the art. Theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention, which is defined solely by the claims. In order that thepresent disclosure can be more readily understood, certain terms arefirst defined. Additional definitions are set forth throughout thedetailed description.

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), or 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unlessspecifically stated otherwise, an alkyl group is optionally substitutedby at least one of the following substituents: halo, cyano, nitro, oxo,thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2), and —S(O)_(t)N(R^(a))₂(where t is 1 or 2), in which each R^(a) is independently hydrogen,alkyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) in which each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atoms (e.g., C₂ alkynylene). In other embodiments, analkynylene comprises five to eight carbon atoms (e.g., C₅-C₈alkynylene). In other embodiments, an alkynylene comprises two to fivecarbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises three to five carbon atoms (e.g., C₃-C₅alkynylene). Unless stated otherwise specifically in the specification,an alkynylene chain is optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), in which each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl, where R^(c) is an alkynylene chain as defined above.The carbocyclyl part of the carbocyclylalkynyl radical is optionallysubstituted as described above for a carbocyclyl group. In someembodiments the carbocyclyl group is a cycloalkyl group. The alkynylenechain part of the carbocyclylalkynyl radical is optionally substitutedas defined above for an alkynylene chain.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to:

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s).

Examples of such heterocyclyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen atom, andwhere the point of attachment of the heterocyclyl radical to the rest ofthe molecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, imidazolinyl, imidazolidinyl, pyrazolidinyl,1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and 1-pyrrolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpho-linyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s).

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]-thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]-cinnolinyl,6,7-dihydro-5H-benzo[6,7]-cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydro-cycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexa-hydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naph-thyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydro-benzo[h]quinazolinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]-pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoro-methyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans). Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” and “aryl,optionally substituted” mean that the aryl radical may or may not besubstituted and that the description includes both substituted arylradicals and aryl radicals having no substitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedheterocyclic derivative compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates. See, e.g.,Berge et al., Pharmaceutical Salts, 66 J. Pharm. Sci. 1 (1997). Acidaddition salts of basic compounds may be prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce thesalt according to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methyl-glucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., 1997.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, “prodrug” refers to a precursor of abiologically active compound that is pharmaceutically acceptable. Aprodrug may be inactive (or have partial or different activity) whenadministered to a subject, but is converted in vivo to the desiredactive compound, for example, by hydrolysis. A prodrug compound mayoffer advantages of solubility, tissue compatibility, or delayed releasein a mammalian organism. The term “prodrug” is also meant to include anycovalently bonded carriers, which release the active compound in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of anactive compound, as described herein, may be prepared by modifyingfunctional groups present in the active compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent active compound. Prodrugs include compounds wherein ahydroxy, amino or mercapto group is bonded to any group that, when theprodrug of the active compound is administered to a mammalian subject,cleaves to form a free hydroxy, free amino or free mercapto group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol or amine functionalgroups in the active compounds and the like. See, e.g., Bundgard, DESIGNOF PRODRUGS, at 7-9, 21-24 (Elsevier, Amsterdam, 1985); Higuchi et al.,Pro-drugs as Novel Delivery Systems, 14 A.C.S. Symposium Series inBIOREVERSIBLE CARRIERS IN DRUG DESIGN (Roche, Ed.; Am. Pharm. Assoc. &Pergamon Press, 1987).

The compounds of the present disclosure may optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I), orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention. Accordingly, unless otherwise stated, structures depictedherein are intended to include compounds which differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement of ahydrogen by a deuterium or tritium, or the replacement of a carbon by¹³C- or ¹⁴C-enriched carbon are within the scope of the presentdisclosure. In certain embodiments, the compounds disclosed herein havesome or all of the ¹H atoms replaced with ²H atoms. The methods ofsynthesis for deuterium-containing substituted heterocyclic derivativecompounds are known in the art and include, by way of non-limitingexample only, the following synthetic methods.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing substituted heterocyclic derivative compounds.Large numbers of deuterium-containing reagents and building blocks areavailable commerically from chemical vendors, such as Aldrich ChemicalCo. Deuterium-transfer reagents suitable for use in nucleophilicsubstitution reactions, such as iodomethane-d₃ (CD₃I), are readilyavailable and may be employed to transfer a deuterium-substituted carbonatom under nucleophilic substitution reaction conditions to the reactionsubstrate. The use of CD₃I is illustrated, by way of example only, inthe following reaction schemes:

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the following reaction schemes:

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thefollowing reaction schemes:

In one embodiment, the compounds disclosed herein contain one deuteriumatom. In another embodiment, the compounds disclosed herein contain twodeuterium atoms. In another embodiment, the compounds disclosed hereincontain three deuterium atoms. In another embodiment, the compoundsdisclosed herein contain four deuterium atoms. In another embodiment,the compounds disclosed herein contain five deuterium atoms. In anotherembodiment, the compounds disclosed herein contain six deuterium atoms.In another embodiment, the compounds disclosed herein contain more thansix deuterium atoms. In another embodiment, the compound disclosedherein is fully substituted with deuterium atoms and contains nonon-exchangeable ¹H hydrogen atoms. In one embodiment, the level ofdeuterium incorporation is determined by synthetic methods in which adeuterated synthetic building block is used as a starting material.

Substituted Heterocyclic Derivative Compounds

Substituted heterocyclic derivative compounds are described herein thatare bromodomain inhibitors. These compounds, and compositions comprisingthese compounds, are useful for the treatment of cancer and neoplasticdisease. The compounds described herein may, therefore, be useful fortreating NUT midline carcinoma, prostate cancer, breast cancer, bladdercancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Formula I having the structure:

wherein

-   -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X5 is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl        or alkoxy;    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein W is a bond, —O—, —S—, or —NH—, and X is selected from        alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        or heteroarylalkyl; and    -   G is described by:

-   -   wherein,        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or optionally, when R²³ is hydrogen, R²⁵ is not            hydrogen and R²⁶ is not hydrogen or halogen, R²⁵ and R²⁶            join to form an optionally substituted ring;    -   provided that the compound of Formula I is not        4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-methylisoquinolin-1(2H)-one,        2-methyl-4-(2-oxoindolin-6-yl)isoquinolin-1(2H)-one,        4-methyl-6-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2H-benzo[b][1,4]oxazin-3        (4H)-one, nor        4-(1′-cyclobutyl-4H-spiro[benzo[d][1,3]dioxine-2,4′-piperidine]-6-yl)-2-methylisoquinolin-1(2H)-one.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one N atom. Another embodiment provides the compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein ring A is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S atom. Another embodiment provides the compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein ring A is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one N atom.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one S atom.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X5 is C—R¹⁵ and R¹⁵ isas described above. Another embodiment provides the compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein X6 is C—R¹⁶and R¹⁶ is as described above. Another embodiment provides the compoundof Formula I, or a pharmaceutically acceptable salt thereof, wherein X2is C—R¹² and R¹² is as described above. Another embodiment provides thecompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein X5 is N. Another embodiment provides the compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein X6 is N. Anotherembodiment provides the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X2 is N. Another embodiment providesthe compound of Formula I, or a pharmaceutically acceptable saltthereof, wherein X2 is C—R¹², X5 is C—R¹⁵, and X6 is C—R¹⁶, wherein R¹²,R¹⁵, and R¹⁶ are as described above.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is:

wherein

-   -   R¹ is hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R² is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R³ is independently hydrogen, halogen, alkyl, alkoxy,        alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        and    -   R¹², R¹⁵, and R¹⁶ are as described above.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A, optionally,excludes:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is:

and wherein R¹, R², R¹², R¹⁵, and R¹⁶ are as described above.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is:

wherein R¹, R², and R¹⁶ are as described above.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is hydrogen or—W—X, wherein W is a —O—, —S—, or —NH—, and X is alkyl, alkynyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl-alkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R¹ is hydrogen,alkyl, alkylsulfonyl, alkylsulfinyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R² alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is —W—X, wherein Wis —O— and X is alkyl aryl, cycloalkyl, or cycloalkylalkyl; R¹ ishydrogen or alkyl; and R² is alkyl.

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is:

Another embodiment provides the compound of Formula I, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is:

At least one embodiment provides a compound of Formula II, or apharmaceutically acceptable salt thereof, Formula II represented by

wherein

-   -   Ring B is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, in which Y is a bond,        —CH₂—, or —CH(C₁-C₄ alkyl)-, and Z is —SO₂R^(b),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,        —CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂,        —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or        —N(R^(a))SO₃R^(b), and wherein each R^(a) is independently        hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        and    -   G is:

-   -   wherein        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl; and        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl, or,    -   optionally, when R²³ is hydrogen, R²⁵ is not hydrogen (i.e., R²⁵        is halogen, alkyl, alkoxy, or alkenyl), and R²⁶ is not hydrogen        or halogen (i.e., R²⁶ is alkyl, alkoxy, aminoalkyl, or alkenyl),        then R²⁵ and R²⁶ join to form an optionally substituted ring.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is:

wherein R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; each R³ is independently hydrogen, halogen, alkyl,alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; and wherein R¹², R¹³, and R¹⁶ are asdescribed above.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is:

in which R¹, R³, R¹², R¹³, and R¹⁶ are as described above.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is illustratedby a formula:

wherein R¹, R³, and R¹³ are as described above.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S or N atom. Another embodiment provides the compound ofFormula II, or a pharmaceutically acceptable salt thereof, wherein ringB is an optionally substituted 5- or 6-membered heterocyclyl ringcontaining at least one S or N atom.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one N atom. Another embodiment provides the compound of FormulaII, or a pharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one N atom.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one S atom. Another embodiment provides the compound of FormulaII, or a pharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S atom.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein X2 is N. Anotherembodiment provides the compound of Formula II, or a pharmaceuticallyacceptable salt thereof, wherein X3 is N. Another embodiment providesthe compound of Formula II, or a pharmaceutically acceptable saltthereof, wherein X6 is N. Another embodiment provides the compound ofFormula II, or a pharmaceutically acceptable salt thereof, wherein X2 isC—R¹² and R¹² is as described above. Another embodiment provides thecompound of Formula II, or a pharmaceutically acceptable salt thereof,wherein X3 is C—R¹³ and R¹³ is as described above. Another embodimentprovides the compound of Formula II, or a pharmaceutically acceptablesalt thereof, wherein X6 is C—R¹⁶ and R¹⁶ is as described above. Anotherembodiment provides the compound of Formula II, or a pharmaceuticallyacceptable salt thereof, wherein X2 is C—R¹², X3 is C—R¹³, and X6 isC—R¹⁶, wherein R¹², R¹³, and R¹⁶ are as described above.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z, in whichY is a bond or —CH₂—, and Z is —SO₂R^(b)—N(R^(a))SO₂R^(b), or—SO₂N(R^(a))₂, each R^(a) is independently hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, and R^(b) is alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; wherein R¹ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and wherein R³ ishydrogen, halogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkoxy,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z in which Yis a bond or —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), each R^(a) isindependently hydrogen or alkyl, and R^(b) is alkyl; wherein R¹ isalkyl, cycloalkylalkyl, or aralkyl; and wherein R³ is hydrogen, halogen,alkyl, or alkoxy.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is —W—X, wherein Wis —O—, and X is alkyl aryl, cycloalkyl, or cycloalkylalkyl; wherein R¹is hydrogen or alkyl; and wherein R² is alkyl.

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is:

Another embodiment provides the compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R¹⁶ is:

At least one embodiment provides a compound of Formula III, or apharmaceutically acceptable salt thereof, Formula III represented by:

wherein

-   -   Ring C is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one O, S or N atom;    -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, wherein R¹³ is —Y—Z, in which Y is selected        from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)- and Z is selected from        —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,        —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),        —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂,        —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), and wherein each R^(a) is        independently selected from hydrogen, alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl, and R^(b) is selected from        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; and    -   G is:

-   -   wherein,        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or optionally, when R²³            is alkyl, R²² and R²³ join to form an optionally substituted            ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or optionally, when R²³ is hydrogen, R²⁵ is not            hydrogen and R²⁶ is not hydrogen or halogen, then R²⁵ and            R²⁶ form an optionally substituted ring;    -   provided that the compound of Formula III is neither        4-(2-ethyl-5-(methyl-sulfonyl)        benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one, nor        4-(2-cyclopropyl-5-(methyl-sulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R¹², R¹³, and R¹⁴ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and wherein R¹², R¹³, and R¹⁴ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹, R³, R¹², R¹³, and R¹⁴ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C:

wherein R¹, R³, R¹², R¹³, and R¹⁴ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹, R³, and R¹³ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹, R³, and R¹³ are as described above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is:

wherein R¹ and R¹³ are as described above.

An alternative embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein, optionally, ring C isnot:

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z, in whichY is a bond, or —CH₂— and Z is selected from —SO₂R^(b),—N(R^(a))SO₂R^(b), or —SO₂N(R^(a))₂, and in which each R^(a) isindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and wherein each remaining substituent is otherwise asdescribed above.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z in which Yis a bond, or —CH₂— and Z is selected from —SO₂R^(b), or—N(R^(a))SO₂R^(b), in which each R^(a) is independently hydrogen oralkyl, R^(b) is alkyl, R¹ is alkyl, and R³ is alkyl, cycloalkyl, oraryl.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein ring C is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one O atom. Another embodiment provides the compound of FormulaIII, or a pharmaceutically acceptable salt thereof, wherein ring C is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S atom. Another embodiment provides the compound of FormulaIII, or a pharmaceutically acceptable salt thereof, wherein ring C is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one N atom.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein X2 is N. Anotherembodiment provides the compound of Formula III, or a pharmaceuticallyacceptable salt thereof, wherein X3 is N. Another embodiment providesthe compound of Formula III, or a pharmaceutically acceptable saltthereof, wherein X4 is N.

Another embodiment provides the compound of Formula III, or apharmaceutically acceptable salt thereof, wherein X2 is C—R¹², whereinR¹² is as described above. Another embodiment provides the compound ofFormula III, or a pharmaceutically acceptable salt thereof, wherein X3is C—R¹³, wherein R¹³ is as described above. Another embodiment providesthe compound of Formula III, or a pharmaceutically acceptable saltthereof, wherein X4 is C—R¹⁴ wherein R¹⁴ is as described above. Anotherembodiment provides the compound of Formula III, or a pharmaceuticallyacceptable salt thereof, wherein X2 is C—R¹², X3 is C—R¹³, and X4 isC—R¹⁴ wherein R¹², R¹³, and R¹⁴ are as described above.

One embodiment provides a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof, Formula IV represented by:

wherein

-   -   each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;    -   R¹³ is —Y—Z, in which Y is selected from a bond, —CH₂—, or        —CH(C₁-C₄ alkyl)- and Z is selected from —SO₂R^(b),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,        —CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂,        —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or        —N(R^(a))SO₃R^(b), wherein each R^(a) is independently hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R^(b) is        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   R¹⁶ is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   G is:

-   -   wherein,        -   R²² is alkyl;        -   R²³ is hydrogen, halogen, or alkyl; or,        -   optionally, when R²³ is alkyl, R²² and R²³ join to form an            optionally substituted ring;        -   R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;        -   R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or            alkenyl; or        -   optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, and            R²⁶ is neither hydrogen nor halogen, then R²⁵ and R²⁶ join            to form an optionally substituted ring.

Another embodiment provides the compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula IV, or apharmaceutically acceptable salt thereof, wherein G is:

Another embodiment provides the compound of Formula IV that is FormulaIVa, or a pharmaceutically acceptable salt thereof, wherein R¹³, R¹⁴,and G are as described above:

Another embodiment provides the compound of Formula IVa, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z, in whichY is a bond or —CH₂—, and Z is —SO₂R^(b)—N(R^(a))SO₂R^(b), or—SO₂N(R^(a))₂, in which each R^(a) is independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R^(b) is alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and R¹⁶ is alkyl,alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides the compound of Formula IVa, or apharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z, in whichY is a bond or —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), in which eachR^(a) is independently hydrogen or alkyl, and R^(b) is alkyl; andwherein R¹⁶ is selected from alkyl or cycloalkylalkyl.

At least one embodiment provides a compound of Formula Va, or apharmaceutically acceptable salt thereof, having the structure:

wherein

-   -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X5 is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl        or alkoxy; and    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

One embodiment provides a compound of Formula Vb, or a pharmaceuticallyacceptable salt thereof, Formula Vb represented by:

wherein

-   -   Ring B is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one S or N atom, or an optionally        substituted 5- or 6-membered heterocyclyl ring containing at        least one S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, wherein Y is selected        from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-, and Z is selected from        —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,        —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),        —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂,        —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), each R^(a) is        independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,        aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, and R^(b) is alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,        wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula Vc, or apharmaceutically acceptable salt thereof:

wherein

-   -   Ring C is an optionally substituted 5- or 6-membered heteroaryl        ring containing at least one O, S or N atom;    -   X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   X3 is N or C—R¹³, in which R¹³ is —Y—Z, in which Y is a bond,        —CH₂—, or —CH(C₁-C₄ alkyl)-, and Z is selected from —SO₂R^(b),        —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,        —CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂,        —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or        —N(R^(a))SO₃R^(b), wherein each R^(a) is independently hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R^(b) is        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   X4 is N or C—R¹⁴, in which R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy.

At least on embodiment provides a compound of Formula Vd, or apharmaceutically acceptable salt thereof,

wherein

-   -   each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;    -   R¹³ is —Y—Z, in which Y is a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-,        and Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b),        —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂,        —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),        —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein        each R^(a) is independently hydrogen, alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl, and R^(b) is alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   R¹⁶ is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula Ve, or apharmaceutically acceptable salt thereof:

wherein

-   -   J is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z, in which Y is a bond, —CH₂—, or —CH(C₁-C₄alkyl)-,        and Z is —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,        —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,        —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, in which        each R²¹ is independently alkyl, cycloalkyl, cycloalkylalkyl,        aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, and wherein each R²² is independently hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   K is N or C—R¹⁴, in which R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   Q is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy; and    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a        bond, —O—, —S—, or —NH—, and X is alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

At least one embodiment provides a compound of Formula VI, or apharmaceutically acceptable salt thereof, in which Formula VI is:

wherein

-   -   n is 0 to 4; m is 0 or 1;    -   R^(A) is a halogen, C1-3 alkyl, or C1-3 alkoxy;    -   J is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z, in which Y is a bond, —CH₂—, or —CH(C₁-C₄alkyl)-,        and Z is —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,        —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,        —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, wherein        each R²¹ is independently alkyl, cycloalkyl, cycloalkylalkyl,        aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, and each R²² is independently hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.    -   K is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   Q is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy; and    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a        bond, —O—, —S—, or —NH—, and X is alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

In some embodiments, the substituted heterocyclic derivative compounddisclosed herein has the structure and chemical name provided in Table1, in which “Ex. No.” refers to the Example describing the synthesis ofthe compound.

TABLE 1 Ex. No Structure Name 1

2-methyl-4-(2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)isoquinolin-1-one 2

4-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-2-methylisoquinolin-1-one 3

5-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)-1,3-dimethylpyridin-2-one 4

4-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)-2-methylisoquinolin-1-one 5

5-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3- dimethylpyridin-2-one 6

4-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2- methylisoquinolin-1-one 7

4-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-one 8

5-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one 9

1,3-dimethyl-5-[2-methyl-1,1-dioxo-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazol-6- yl]pyridin-2-one 10

2-methyl-4-[2-methyl-1,1-dioxo-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazol-6- yl]isoquinolin-1-one 11

5-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3- dimethylpyridin-2-one 12

5-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1-methylpyridin-2-one 13

4-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one 14

4-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one 15

5-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-1,3-dimethylpyridin-2-one 16

5-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-1,3-dimethylpyridin-2-one 17

N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol-4-yl]methanesulfonamide 18

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indol-4-yl]methanesulfonamide 19

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydroindol-4-yl]methanesulfonamide 20

N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-2,3-dihydroindol-4-yl]methanesulfonamide 21

5-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3-dimethylpyridin-2-one 22

N-[2-(1,5-dimethyl-6-oxopyridin-3-yl)-9-[(4-fluorophenyl)methyl]-8-methylpurin-6- yl]methanesulfonamide 23

5-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3-dimethylpyridin-2-one 24

4-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one 25

1,3-dimethyl-5-(5-methylsulfonyl-2-phenyl-1-benzofuran-7-yl)pyridin-2-one 26

2-methyl-4-(5-methylsulfonyl-2-phenyl-1-benzofuran-7-yl)isoquinolin-1-one 27

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzotriazol-4-yl]ethanesulfonamide 28

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]benzotriazol-4- yl]ethanesulfonamide 29

4-[6-(cyclopropylmethoxy)-1-methyl-3- methylsulfonylindazol-5-yl]-2-methylisoquinolin-1-one 30

4-[6-(cyclopropylmethoxy)-3-ethylsulfonyl-1-methylindazol-5-yl]-2-methylisoquinolin-1-one 31

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzoimidazol-4-yl]methanesulfonamide 32

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4- yl]methanesulfonamide 33

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4- yl]ethanesulfonamide 34

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide 35

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4- yl]methanesulfonamide 36

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4- yl]ethanesulfonamide 37

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylbenzimidazol-4- yl]methanesulfonamide 38

N-[1-[(4-fluorophenyl)methyl]-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methylbenzimidazol- 4-yl]methanesulfonamide39

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4- yl]methanesulfonamide 40

N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide 41

N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4- yl]ethanesulfonamide 42

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indazol-4-yl]ethanesulfonamide 43

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]indazol-4- yl]ethanesulfonamide 44

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4- yl]methanesulfonamide 45

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4- yl]methanesulfonamide 46

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(2R)-1-methoxypropan-2-yl]-2-methylbenzimidazol-4- yl]methanesulfonamide 47

N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide 48

N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide 49

4-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-2- methylisoquinolin-1-one 50

5-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-1,3- dimethylpyridin-2-one 51

N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]propane-2-sulfonamide 52

N-[2-cyclopentyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide 53

N-[2-cyclopentyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide 54

N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-3-methylbenzimidazol-5- yl]ethanesulfonamide 55

N-[2-cyclopropyl-3-methyl-7-(2-methyl-1-oxoisoquinolin-4-yl)benzimidazol-5- yl]ethanesulfonamide 56

5-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazol-7-yl]-1,3-dimethylpyridin-2-one 57

N-[2-cyclopentyl-7-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5- yl]ethanesulfonamide 58

5-[6-(cyclopropylmethoxy)-1-methyl-3- methylsulfonylindazol-5-yl]-1,3-dimethylpyridin-2-one 59

5-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-3-methoxy-1- methylpyridin-2-one 60

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamide 61

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylimidazo[4,5-c]pyridin-4- yl]methanesulfonamide 62

N-[1-(2,4-difluorophenyl)methyl]-6-(1,5- dimethyl-6-oxopyridin-3-yl)-2-methylimidazo[4,5-c]pyridin-4- yl]methanesulfonamide 63

5-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazol-7-yl]-3-methoxy-1- methylpyridin-2-one 64

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-4- yl]methanesulfonamide 65

N-[3-fluoro-1-[(4-fluorophenyl)methyl]-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)indazol-4- yl]methanesulfonamide 66

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4- yl]methanesulfonamide 67

5-(3-benzyl-2-methyl-7- methylsulfonylbenzimidazol-5-yl)-1,3-dimethylpyridin-2-one 68

5-(3-benzyl-7-ethylsulfonyl-2- methylbenzimidazol-5-yl)-3-methoxy-1-methylpyridin-2-one 69

5-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2-methylbenzamidazol-5-yl]-1,3- dimethylpyridin-2-one 70

5-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2-methylbenzimidazol-5-yl]-3-methoxy-1- methylpyridin-2-one 71

5-[3-(cyclopropylmethyl)-2-methyl-7-methylsulfonylbenzimidazol-5-yl]-1,3- dimethylpyridin-2-one 72

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethoxybenzimidazol-4- yl]methanesulfonamide 73

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4- yl]methanesulfonamide 74

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethylbenzimidazol-4- yl]methanesulfonamide 75

5-(1-ethyl-4-methylsulfonylindol-2-yl)-1,3- dimethylpyridin-2-one 76

5-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]-1,3-dimethylpyridin-2-one 77

5-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]-1,3-dimethylpyridin-2-one 78

4-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]-2-methylisoquinolin-1-one 79

N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]methanesulfonamide 80

N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1-benzofuran-5-yl]methanesulfonamide 81

N-[9-(cyclopropylmethyl)-2-(1,5-dimethyl-6-oxopyridin-3-yl)-8-methylpurin-6- yl]methanesulfonamide 82

N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]ethanesulfonamide 83

N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-phenyl-1-benzofuran-5-yl]methanesulfonamide 84

N-[7-(2-methyl-1-oxoisoquinolin-4-yl)-2-phenyl-1-benzofuran-5-yl]methanesulfonamide 85

8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2,3-dihydro-1H- indolizin-5-one 86

N-[4-(2,4-difluorophenoxy)-3-(6-methyl-5-oxo-2,3-dihydro-1H-indolizin-8- yl)phenyl]methanesulfonamide 87

8-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2,2,6-trimethyl-1,3-dihydroindolizin-5-one 88

N-[4-(2,4-difluorophenoxy)-3-(2,2,6-trimethyl-5-oxo-1,3-dihydroindolizin-8- yl)phenyl]methanesulfonamide 89

8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,1-difluoro-6-methyl-2,3- dihydroindolizin-5-one90

8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-fluoro-6-methyl-2,3- dihydro-1H-indolizin-5-one91

5-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]-3-methoxy-1-methylpyridin-2-one 92

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide 93

N-[1-(cyclopropylmethyl)-6-(5-methoxy-1- methyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4- yl]methanesulfonamide 94

N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide 95

N-[1-butyl-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4- yl]methanesulfonamide 96

5-[3-(cyclopropylmethyl)-2-methyl-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 97

5-[3-(cyclopropylmethyl)-2-ethoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 98

5-[3-(cyclopropylmethyl)-2-ethoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-3-methoxy-1-methylpyridin-2-one 99

5-[3-(cyclopropylmethyl)-2-methoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 100

5-[2-cyclopropyl-5-(ethylsulfonylmethyl)-1,3-benzoxazol-7-yl]-3-methoxy-1- methylpyridin-2-one 101

N-[3-(cyclopropylmethyl)-5-(1,5-dimethyl-6-oxopyridin-3-yl)-2-oxo-1,3-benzoxazol-7- yl]methanesulfonamide 102

N-[5-(1,5-dimethyl-6-oxopyridin-3-yl)-3-[(4-fluorophenyl)methyl]-2-oxo-1,3-benzoxazol-7- yl]methanesulfonamide 103

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4- yl]ethanesulfonamide 104

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4-yl]methanesulfonamide 105

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-4- yl]ethanesulfonamide 106

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4-yl]ethanesulfonamide

In some embodiments, the substituted heterocyclic derivative compounddisclosed herein has the structure provided in Table 2.

TABLE 2

Preparation of the Substituted Heterocyclic Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including, for example,Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis.,including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park,UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada),Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatises detail the synthesis of reactants useful in the preparation ofcompounds described herein, or provide references to articles thatdescribe the preparation. See, e.g., SYNTHETIC ORGANIC CHEM. (John Wiley& Sons, Inc., NY); Sandler et al., ORGANIC FUNCTIONAL GROUP PREPARATIONS(2nd Ed., Acad. Press, N Y, 1983); House, MODERN SYNTHETIC REACTIONS(2nd Ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972); Gilchrist,HETEROCYCLIC CHEM. (2nd Ed., John Wiley & Sons, N Y, 1992); March, ADV.ORGANIC CHEM.: REACTIONS, MECH. & STRUCTURE (4th Ed., Wiley-Intersci.,NY, 1992). Additional suitable reference books and treatises detail thesynthesis of reactants useful in the preparation of compounds describedherein, or provide references to articles that describe suchpreparations. See, e.g., Fuhrhop & Penzlin, ORGANIC SYNTHESIS: CONCEPTS,METHODS, STARTING MATERIALS: SECOND, REVISED & ENLARGED ED. (John Wiley& Sons ISBN: 3-527-29074-5, 1994); Hoffman, ORGANIC CHEM., ANINTERMEDIATE TEXT (Oxford Univ. Press, ISBN 0-19-509618-5, 1996);Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS: GUIDE TO FUNCTIONAL GROUPPREPARATIONS (2nd Ed., Wiley-VCH, ISBN: 0-471-19031-4, 1999); Otera(Ed.), MODERN CARBONYL CHEM. (Wiley-VCH, ISBN: 3-527-29871-1, 2000);Patai, PATAI'S 1992 GUIDE TO THE CHEM. OF FUNCTIONAL GROUPS (Intersci.ISBN: 0-471-93022-9, 1992); Solomons, ORGANIC CHEM. (7th Ed., John Wiley& Sons, ISBN: 0-471-19095-0, 2000); Stowell, INTERMEDIATE ORGANIC CHEM.(2nd Ed. Wiley-Intersci., ISBN: 0-471-57456-2, 1993); INDUS. ORGANICCHEM.: STARTING MATS. & INTERMEDIATES: AN ULLMANN'S ENCYCLO. (John Wiley& Sons, ISBN: 3-527-29645-X, 1999), in 8 vols.; ORGANIC REACTIONS (JohnWiley & Sons, 1942-2000), in over 55 volumes; CHEM. OF FUNCTIONAL GROUPS(John Wiley & Sons), in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted heterocyclic derivativecompounds described herein is Stahl & Wermuth, HANDBOOK OFPHARMACEUTICAL SALTS (Verlag Helvetica Chimica Acta, Zurich, 2002).

General methods for the synthesis of substituted heterocyclicderivatives are provided in, but not limited to, the followingreferences: WO 2009/158396; WO 2005/63768; WO 2006/112666; Briet et.al., 58 Tetrahedron 5761 (2002); WO 2008/77550; WO 2008/77551; WO2008/77556; WO 2007/12421; WO 2007/12422; US 2007/99911; WO 2008/77550;Havera et al., 42 J. Med. Chem. 3860 (1999); WO 2004/29051; and US2009/0054434. Additional examples of the synthesis of substitutedheterocyclic derivatives are found in the following references: WO2012/171337; WO 2011/044157; WO 2009/097567; WO 2005/030791; EP 203216;Becknell et al., 21 Bioorg. & Med. Chem. Letters 7076 (2011); Svechkarevet al., 770

201 (2007); Coskun et al., 35 Synth. Commc'ns 2435 (2005); Alvarez etal., 15 Sci. Synth. 839 (2005); Kihara et al., 53 Heterocycles 359(2000); Couture et al., 7 J. Chem. Soc'y 789 (1999); Kihara et al., 48Heterocycles 2473 (1998); Couture et al., 52 Tetrahedron 4433 (1996);Couturre et al., 37 Tetrahedron Letters 3697 (1996); Natsugari et al.,38 J. Med. Chem. 3106 (1995); Moehrle et al., 321 Archiv der Pharm. 759(1988); Gore et al., 3 J. Chem. Soc'y 481 (1999); Narasimhan et al., 3J. Chem. Soc'y, Chem. Commc'ns 191 (1987); Henry et al., 40 J. Org.Chem. 1760 (1975); Berti, 90 Gazzetta Chimica Italiana 559 (1960); Bertiet al., 49 Annali di Chimica 2110, 1253 (Rome, Italy, 1959); WO2012/000595; Couture et al., 52 Tetrahedron 4433 (1996); WO 2010/069504;WO 2010/069504; WO 2006/030032; WO 2005/095384; US 2005/0222159; WO2013/064984; Mishra et al., 2013 Eur. J. Org. Chem. 693 (2013); Vachhaniet al., 69 Tetrahedron 359 (2013); Xie et al., 45 Eur. J. Med. Chem. 210(2010); Mukaiyama et al., 15 Bioorg. & Med. Chem. 868 (2007); JP2005/089352; Wang et al., 9 Molecules 574 (2004); WO 2000/023487; US2006/0287341; CN 103183675; Hares et al., 32 Egyptian J. Pharm. Sci. 303(1991); DE 2356005; DE 2133898; DE 2133998; DE 2011970; U.S. Pat. No.3,816,422; Staehle et al., 8 Justus Liebigs Annalen der Chem. 1275(1973).

In some embodiments, the substituted heterocyclic derivative compoundsdisclosed herein are prepared by the general synthetic routes describedbelow in Schemes 1-9. These schemes are intended to exemplary to one ofskill in the art and are not limiting. Additional methods for thesynthesis of the substituted heterocyclic derivative compounds disclosedherein are readily available to one of skill in the art.

A method for preparing compounds of Formulas I-IV is provided in Scheme1:

According to Scheme 1, the compound6-bromo-2-methylisoquinolin-1(2H)-one (1-1) is subjected to apalladium-catalyzed cross coupling reaction to provide isoquinolinone(1-2). Bromination under acidic conditions provides compound (1-3).Further palladium-catalyzed cross coupling reaction with a boronic acid,or ester, provides the isoquinolinone (1-4). Alternatively,palladium-catalyzed cross coupling of compound (1-3) with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneunder the conditions described by Miyaura (Ishiyama et al., 60 J. Org.Chem. 7508 (1995) provides the boron ester (1-5). Furtherpalladium-catalyzed cross coupling reaction of compound (1-5) with asuitable halide provides the isoquinolinone (1-6).

A method for preparing compounds of Formulas I-IV is provided in Scheme2:

As provided in Scheme 2, the compound6-bromo-2-methylisoquinolin-1(2H)-one (2-1) is subjected to apalladium-catalyzed cross coupling reaction with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneto provide boron ester (2-2). Further palladium-catalyzed cross couplingreaction of compound (2-2) with a suitable halide provides compound(2-3). Bromination under acidic conditions provides compound (2-4).Further palladium-catalyzed cross coupling reaction with a boronic acid,or ester, provides the isoquinolinone (2-5).

A method for preparing compounds of Formulas I-IV is provided in Scheme3:

According to the method provided in Scheme 3, the compound5-bromo-pyridin-2-ol derivative (3-1) is subjected to alkylation withmethyl iodide under basic conditions to provide the related5-bromo-1-methylpyridin-2(1H)-one derivative (3-2). Furtherpalladium-catalyzed cross coupling reaction of compound (3-2) with asuitable halide provides compound (3-3).

A method for preparing compounds of Formulas I-IV is further provided inScheme 4:

According to the method for preparing compounds of Formulas I-IV asprovided in Scheme 4, the compound3-amino-5-bromo-1-methylpyridin-2(1H)-one derivative (4-1) is used as astarting material for several routes. In one route, compound (4-1) isdirectly subjected to a palladium-catalyzed cross coupling reaction toprovide pyridone (4-3). The amino group of compound (4-3) is subjectedto a reductive amination with an aldehyde and a reducing agent, such assodium cyanoborohydride, to provide the substituted amino derivativecompound (4-7). A second route involving selective alkylation of theamino group of compound (4-1) begins with protection of the amino groupas the BOC carbamate. Alkylation of the carbamate under basic conditionsfollowed by removal of the BOC carbamate under acidic conditionsprovides the secondary amine compound (4-5). Treatment of (4-5) with asuitable halide under palladium-catalyzed cross coupling conditionsaffords compound (4-6).

Further, a method for preparing benzimidazole compounds of Formula II isprovided in Scheme 5:

Accordingly, in the method for preparing benzimidazole compounds ofFormula II per Scheme 5, the compound 4-bromo2,6-difluoro-1-nitrobenzene (5-1) is subjected to nucleophilicdisplacement with a substituted amine under basic conditions to providea 2-aminonitrobenzene compound (5-2). Further substitution with a thiolprovides compound (5-3). Oxidation of the sulphur of (5-3) with MCPBAfollowed by reduction of the nitro group provides compound (5-5).Cyclocondensation of (5-5) with a carbonyl derivative providesbenzimidazole compound (5-6). Palladium-catalyzed cross coupling ofbromobenzimidazole derivates (5-6) with a boronic acid or ester theprovides the desired product (5-7).

A method for preparing indazole compounds of Formula II is provided inScheme 6:

As per Scheme 6, Bromoindazole derivative (6-1) is subjected tofluorination to provide compound (6-2). Alkylation on nitrogen providesthe substituted indazole (6-3). Palladium-catalyzed cross coupling of(6-3) with a boronic acid or ester provides the desired product (6-5).Reduction of the nitro group provides aniline (6-6) which is thenreacted with sulfonyl chloride to afford sulfonamide (6-7).

A method for preparing benzimidazole compounds of Formula II is providedin Scheme 7:

Using the method for preparing benzimidazole compounds of Formula IIprovided in Scheme 7, the compound 2-aminonitrobenzene compound (5-2) issubjected to nucleophilic displacement with a substituted sulfonamideunder basic conditions to provide nitrobenzene compound (7-2). Reductionof the nitro group provides compound (7-3). Cyclocondensation of (7-3)with a carbonyl derivative provides benzimidazole compound (7-4).Palladium-catalyzed cross coupling of bromobenzimidazole derivates (7-4)with a boronic acid or ester provides the desired product (7-5).

A method for preparing benzimidazole compounds of Formula II is providedin Scheme 8:

In accord with Scheme 8, bromonitrobenzimidazole compound (8-1) isalkylated on nitrogen under basic conditions to provide nitro compound(8-2). Reduction of the nitro group provides compound (8-3). Reaction of(8-3) with a sulphonyl chloride derivative under basic conditionsprovides benzimidazole compound (8-4). Palladium-catalyzed crosscoupling of bromobenzimidazole derivate (8-4) with a boronic acid orester provides the desired product (8-5).

An alternative method for preparing benzimidazole compounds of FormulaII is provided in Scheme 9:

As outlined of Scheme 9, the compound 2-bromo-6-aminonitrobenzene (9-1)is alkylated to afford thiomethyl derivative (9-2). Reduction of thenitro group provides compound (9-3). Cyclocondensation of (9-3) with acarbonyl derivative provides benzimidazole compound (9-4). Compound(9-4) is alkylated on nitrogen under basic conditions to provide sulfide(9-5) which is oxidized with MCPBA to sulfone (9-6). Palladium-catalyzedcross coupling of bromobenzimidazole derivate (9-6) with a boronic acidor ester provides the desired product (9-7).

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Pharmaceutical Compositions

In certain embodiments, a substituted heterocyclic derivative compoundas described herein is administered as a pure chemical or salt thereof.In other embodiments, the substituted heterocyclic derivative compounddescribed herein is prepared in a pharmaceutical composition in whichthe substituted heterocyclic derivative compound is combined with atleast one pharmaceutically acceptable or pharmaceutically suitableexcipient (also referred to herein as a pharmaceutically suitable (oracceptable) carrier, physiologically suitable (or acceptable) excipient,or physiologically suitable (or acceptable) carrier), selected on thebasis of a chosen route of administration and standard pharmaceuticalpractices, as are well known. See, e.g., REMINGTON: SCI. & PRACTICEPHARM. (Gennaro, 21^(st) Ed., Mack Pub. Co., Easton, Pa., 2005).

Accordingly, provided herein are pharmaceutical compositions thatcomprise at least one substituted heterocyclic derivative compound, or astereoisomer, pharmaceutically acceptable salt, hydrate, solvate, orN-oxide thereof, together with at least one pharmaceutically acceptableexcipient. The excipient (or carrier) is acceptable or suitable if theexcipient is compatible with the other active agents or excipients ofthe composition, not deleterious to the recipient (i.e., the subject) ofthe composition, and prepared under good laboratory practices asrequired for the particular dosage form.

One embodiment provides a pharmaceutical composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof.One embodiment provides a pharmaceutical composition comprising acompound of Formula II, or a pharmaceutically acceptable salt thereof.One embodiment provides a pharmaceutical composition comprising acompound of Formula III, or a pharmaceutically acceptable salt thereof.One embodiment provides a pharmaceutical composition comprising acompound of Formula IV, or a pharmaceutically acceptable salt thereof.One embodiment provides a pharmaceutical composition comprising acompound of Formulas Va-Ve, or a pharmaceutically acceptable saltthereof. One embodiment provides a pharmaceutical composition comprisinga compound of Formula VI, or a pharmaceutically acceptable salt thereof.Another embodiment provides a pharmaceutical composition comprising4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one,or a pharmaceutically acceptable salt thereof, from; or4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the substituted heterocyclic derivative compoundas described herein is substantially pure, in that it contains less thanabout 5%, or less than about 1%, or less than about 0.1%, of otherorganic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers are used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. See, e.g., REMINGTON, 2005.

The dose of the composition comprising at least one substitutedheterocyclic derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors that a personskilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome), such as more frequent complete or partial remissions, orlonger disease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Bromodomain Inhibition

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which modify histones atvarious sites.

Epigenetics is the study of heritable changes in gene expression causedby mechanisms other than the underlying DNA sequence. Molecularmechanisms that play a role in epigenetic regulation include DNAmethylation and chromatin/histone modifications.

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. Tremendous compaction is required to package the 3billion nucleotides of the human genome into the nucleus of a cell,where the chromosomes exist in a complex of nucleic acids and proteinscalled chromatin. Histones are the chief protein components ofchromatin. There are a total of six classes of histones (H1, H2A, H2B,H3, H4, and H5) organized into two classes: core histones (H2A, H2B, H3,and H4) and linker histones (H1 and H5). The basic unit of chromatin isa nucleosome, which comprises about 147 base pairs of DNA wrapped arounda core histone octamer which includes two copies each of the corehistones: H2A, H2B, H3, and H4. These nucleosome units are then furtherorganized and condensed by the aggregation and folding of nucleosomes toform the highly condensed chromatin structure. A range of differentstates of condensation are possible, and the tightness of chromatinstructure varies during the cell cycle, being most compact during theprocess of cell division.

Accordingly, chromatin structure plays a critical role in regulatinggene transcription, which cannot occur efficiently in highly condensedchromatin. Chromatin structure is controlled by a series of posttranslational modifications to histone proteins, notably to histones H3and H4, and most commonly within the “histone tails” which extend beyondthe core nucleosome structure. These post translational modificationsinclude acetylation, methylation, phosphorylation, ribosylationsumoylation, ubiquitination, citrullination, deimination, andbiotinylation. In addition to the histone tails, the cores of histonesH2A and H3 can be modified. Given the function of histones in chromatin,histone modifications are integral to diverse biological processes suchas gene expression, DNA replication, DNA repair, and chromosomecondensation.

Histone Acetylation and Bromodomains

Histone acetylation is generally associated with the activation of genetranscription, as the modification is known to loosen the interaction ofthe DNA and the histone octamer by changing the electrostatic state. Inaddition to this physical change, specific proteins are known to bind toacetylated lysine residues within histones in order to functionaccording to the epigenetic code. Bromodomains are small (˜110 aminoacids) distinct domains within proteins that commonly, but notexclusively, bind to acetylated lysine residues in the context ofhistones. Approximately fifty proteins are known to containbromodomains, and they have a range of functions within the cell.

The BET family of bromodomain containing proteins comprises fourproteins (BRD2, BRD3, BRD4, and BRD-t) which contain tandem bromodomainscapable of binding to two acetylated lysine residues that are positionedin close proximity, increasing the specificity of the interaction.Bromodomain-containing proteins that recognize acetylated lysines onhistones (such as BET proteins and non-BET proteins) have beenimplicated in proliferative disease. For example, homozygous BRD4knockout mice are compromised in their ability to maintain an inner cellmass and die shortly after embryo implantation, and heterozygote BRD4knockouts display pre- and postnatal growth defects associated withreduced proliferation rates. BRD4 regulates genes expressed during M/G1,including growth-associated genes, and remains bound to chromatinthroughout the cell cycle. Dey, et al., 20 Mol. Biol. Cell 4899 (2009).BRD4 also associates physically with Mediator and P-TEFb (a heterodimerof Cyclin-dependent kinase 9 [CDK9], cyclin K, cyclin T, or cyclin T2aor T2b) to facilitate transcriptional elongation. Yang et al., 24Oncogene 1653 (2005); Yang et al., 19 Mol. Cell 535 (2005). CDK9 islinked to c-Myc-dependent transcription, and is thus a validated targetin chronic lymphocytic leukemia (CLL). Phelps et al., 113 Blood 2637(2009); Rahl et al., 141 Cell 432 (2010).

Moreover, BRD4 is translocated to the nuclear protein in testis (NUTprotein) in patients with lethal midline carcinoma, an aggressive formof human squamous carcinoma. French et al., 159 Am. J. Pathol. 1987(2001). In vitro analysis with RNAi supports a causal role for BRD4 in arecurrent chromosomal translocation, t(15; 19)(q13; p13.1), whichdefines a lethal midline carcinoma. French et al., 63 Cancer Res. 304(2003). Also, inhibition of the BRD4 bromodomains has been found toresult in growth arrest/differentiation of BRD4-NUT cell lines in vitroand in vivo. Filippakopoulos et al., Selective Inhibition of BETBromodomains, 468 Nature 1067 (2010).

Bromodomain-containing proteins (such as BET proteins) have also beenimplicated in inflammatory diseases. BET proteins (e.g., BRD2, BRD3,BRD4, and BRDT) regulate assembly of histone acetylation-dependentchromatin complexes that control inflammatory gene expression.Hargreaves et al., 138 Cell 129 (2009); LeRoy et al., 30 Molec. Cell 51(2008); Jang et al., 19 Molec. Cell 523 (2005); Yang et al., 19 Molec.Cell 535 (2005). Key inflammatory genes (secondary response genes) aredown-regulated upon bromodomain inhibition of the BET subfamily, andnon-responsive genes (primary response genes) are poised fortranscription. BET bromodomain inhibition protects against LPS-inducedendotoxic shock and bacteria-induced sepsis in vivo. Nicodeme et al.,Suppression of Inflammation by a Synthetic Histone Mimic, 468 Nature1119 (2010).

Bromodomain-containing proteins (such as BET proteins) have also beenfound to play a role in viral infection. For example, BRD4 is implicatedin the primary and persistent phases of human papilloma virus (HPV)infection of basal epithelia, in which BRD4 binding maintains the viralgenome as an extra-chromosomal episome. In some strains of HPV, BRD4binding to the HPV transcriptional activator protein, E2 (early protein2), tethers the viral genome to infected-cell chromosomes. BRD4-E2binding is crucial for both transactivating E2 and repressingtranscription of two HPV oncoproteins (early protein 6 [E6] and earlyprotein 7 [E7]). Disruption of BRD4 or the BRD4-E2 interaction blocksE2-dependent gene activation. BRD4 also functions to tether otherclasses of viral genomes (e.g., Herpes virus, Epstein-Barr virus) to thechromatin of infected cells. Kurg, in DNA REPLICATION—CURRENT ADVANCES613 (Seligmann, ed., InTech, Rijeka, Croatia, 2011).

Bromodomain-containing proteins has also been found to bind toacetylated lysine residues on proteins other than histones. For example,the bromodomain of CREB binding protein transcriptional coactivator(CBP) allows for recognition of p53 with acetylated Lys382. Theinteraction between the bromodomain and acetyl-p53 follows DNA damageand promotes p53-induced transcriptional activation of the CDK inhibitorp21 and cell cycle arrest.

Another novel bromodomain-containing protein is BAZ2B, whose biologicalfunction, is believed to function similarly to ACF1, the DrosophilaBAZ2B ortholog. ACF complexes play roles in establishing regularnucleosome spacing during chromatin assembly and influencing differentremodeling outcomes at target loci.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain-containing protein with acompound of Formula I.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula I.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with acompound of Formula II.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula II.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with acompound of Formula III.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula III.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with acompound of Formula IV.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula IV.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with acompound of Formula Va-Formula Ve.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula Va-Formula Ve.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with acompound of Formula VI.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with a compound of Formula VI.

One embodiment provides a method of regulating gene transcription in acell comprising contacting a bromodomain containing protein with4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-oneor4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprisingcontacting the bromodomain with4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-oneor4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.

Methods of Treatment

Compounds and compositions described herein are generally useful for theinhibition of activity of one or more proteins involved in epigeneticregulation. Thus, at least one embodiment provides a method ofmodulating epigenetic regulation mediated by one or more proteinscontaining acetyl-lysine recognition motifs, also known as bromodomains(e.g., BET proteins, such as BRD2, BRD3, BRD4, or BRDT, and non-BETproteins, such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, or BRPF1) or amutant thereof, by contacting the bromodomain with a substitutedheterocyclic derivative compound described herein. Another embodimentprovides a method of modulating epigenetic regulation by administering asubstituted heterocyclic derivative compound described herein, oradministering a pharmaceutical composition comprising such substitutedheterocyclic derivative compound.

In some embodiments, the substituted heterocyclic derivative compoundsdescribed herein are capable of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4,or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, or BRPF1) or a mutant thereof, in a biological sample, in a manneruseful for a variety of purposes as are known to one of skill in theart. Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, biological specimen storage, andbiological assays.

Some embodiments provide a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4,or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, or BRPF1) or a mutant thereof, in a patient in need of treatment,comprising administering to the patient a substituted heterocyclicderivative compound as described herein, or a pharmaceutical compositioncomprising the compound.

Some embodiments provide a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4,or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, or BRPF1), or mutants thereof, in a biological sample, comprisingthe step of contacting the biological sample with a substitutedheterocyclic derivative compound described herein. In some embodiments,the bromodomain-containing protein is a BET protein. In someembodiments, the BET protein is BRD4.

Some embodiments provide a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4,or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, or BRPF1), or a mutant thereof, in a patient in need of treatment,comprising the step of administering to said patient a substitutedheterocyclic derivative compound (or pharmaceutical compositioncomprising the compound) described herein. In some embodiments, thebromodomain-containing protein is a BET protein. In some embodiments,the BET protein is BRD4.

Diseases and conditions treatable according to the methods of theseembodiments include cancer, neoplastic disease or other proliferativedisorders, or viral infections. Thus, one aspect is a method of treatinga subject having cancer, a neoplastic disease, or other proliferativedisorder; the method comprising administration of a substitutedheterocyclic derivative compound as described herein to the subject. Inone embodiment, a human patient is treated with a pharmaceuticalcomposition comprising a substituted heterocyclic derivative compounddescribed herein, wherein the compound is present in an amountsufficient to measurably inhibit bromodomain-containing protein activity(such as BRD2, BRD3, BRD4, or BRDT activity) in the patient. The amountmay be referred to as an effective amount.

The embodiments further provide a method of treating a subject, such asa human, suffering from cancer, a neoplastic disease, or otherproliferative disorder. The method comprises administering to a subjectin need of such treatment a therapeutically effective amount of at leastone substituted heterocyclic derivative compound described herein, whichfunctions by inhibiting a bromodomain and, in general, by modulatinggene expression, to modulate various cellular effects, in particularinducting or repressing gene expression, arresting cell proliferation,inducing cell differentiation, or inducing apoptosis.

The embodiments further provide a therapeutic method of modulatingprotein methylation, gene expression, cell proliferation, celldifferentiation, or apoptosis in vivo in conditions, illnesses,disorders, infections, or diseases disclosed herein, in particularcancer, inflammatory disease, or viral disease, comprising administeringto a subject in need of such therapy a pharmacologically active ortherapeutically effective amount of at least one substitutedheterocyclic derivative compound described herein, which may beadministered in a pharmaceutical composition.

The embodiments further provide a method of regulating endogenous orheterologous promoter activity by contacting a cell with a substitutedheterocyclic derivative compound described herein. The embodimentsfurther provide a method of regulating endogenous or heterologouspromoter activity by contacting chromatin with a substitutedheterocyclic derivative compound described herein. The embodimentsfurther provide a method of regulating endogenous or heterologouspromoter activity by contacting a viral episome with a substitutedheterocyclic derivative compound described herein.

The embodiments further relate to a method for treating or amelioratingcancer, neoplastic disease, or another proliferative disorder byadministration of an effective amount of a pharmaceutical compositioncomprising a substituted heterocyclic derivative compound a describedherein, to a mammal, in particular a human, in need of such treatment.In some aspects, the disease to be treated by the methods of the presentembodiments is cancer.

In certain embodiments, the cancer is NUT midline carcinoma, prostatecancer, breast cancer, bladder cancer, lung cancer, melanoma, orglioblastoma.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Formula II, or a pharmaceuticallyacceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Formula III, or a pharmaceuticallyacceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising at least one compound selected from Formula Va toFormula Ve, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Formula VI, or a pharmaceuticallyacceptable salt thereof.

One embodiment provides a method of treating a cancer patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising compound, or a pharmaceutically acceptable saltthereof, selected from4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one,or4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.

Other embodiments and uses will be apparent to one of ordinary skill inthe art in light of the present disclosures. The following examples areprovided merely as illustrative of various embodiments and shall not beconstrued to limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants (J) are reported in Hertz. For ¹H NMRspectra, the solvent peak was used as the reference peak.

Example 1 2-methyl-4-(2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)isoquinolin-1-one Step 1:6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide

To a solution of 6-bromo-2,3-dihydro-1,2-benzothiazole 1,1-dioxide (100mg, 0.4 mmol) in DMF (3 ml) at room temperature (RT) was added NaH (18mg, 0.45 mmol). The mixture was stirred for 10 min and methyl iodide (30μL, 0.5 mmol) was then added dropwise. The reaction was stirredovernight. The contents were poured over a precooled saturated ammoniumchloride solution (10 mL). The mixture was extracted with EtOAc (3×7mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (20%-100% EtOAc/Hexane) to provide the titlecompound (89 mg, 84%). LCMS: 261.9 [M+H]⁺.

Step 2:2-methyl-4-(2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)isoquinolin-1-one

A mixture of2-methyl-4-(4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl)isoquinolin-1-one(25 mg, 0.09 mmol), 6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide(23 mg, 0.09 mmol), K₃PO₄ (45 mg, 0.22 mmol) and Pd(dppf)Cl₂ (7 mg, 0.01mmol) in dioxane (1 mL) and H₂O (0.1 mL) was degassed with N₂ for 10 minand then stirred at 70° C. for 2 hr. The reaction mixture was dilutedwith EtOAc (5 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by normal phase silica gelcolumn chromatography to give the title compound (22 mg, 73%). ¹H NMR(DMSO-d6, 400 MHz): δ 8.35 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.80 (dd,J₁=7.9 Hz, J₂=1.3 Hz, 1H), 7.72 (m, 2H), 7.64 (s, 1H), 7.58 (m, 1H),7.43 (d, J=8.1 Hz, 1H), 4.49 (s, 2H), 3.58 (s, 3H), 2.86 (s, 3H). LCMS:341.0 [M+H]⁺.

Example 24-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 1, bysubstituting 6-bromo-2,3-dihydro-1,2-benzothiazole 1,1-dioxide for6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide in step 2. ¹H NMR(DMSO-d6, 400 MHz): δ 8.35 (d, J=7.4 Hz, 1H), 7.91 (m, 1H), 7.85 (m,1H), 7.72 (m, 3H), 7.62 (s, 1H), 7.58 (m, 1H), 7.43 (d, J=8.4 Hz, 1H),4.49 (m, 2H), 3.58 (s, 3H). LCMS: 327.05 [M+H]⁺.

Example 35-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)-1,3-dimethylpyridin-2-oneStep 1: 5-bromo-4-fluoro-2-methylbenzenesulfonyl chloride

1-bromo-2-fluoro-4-methylbenzene (5 g, 26.45 mmol) was added dropwise toClSO₃H (15.5 g, 133.62 mmol) at 0° C. over 15 min. The mixture wasstirred at 0° C. for 45 min. The mixture was poured into ice-water (30mL) at 0° C. and extracted with EA (20 mL×3). The combined organiclayers were dried, filtered and concentrated to give the title compound(6.2 g, 81%) as a gray solid which was used in the next step withoutfurther purification. ¹H NMR (DMSO-d6, 400 MHz): δ 7.90 (d, J=7.6 Hz,1H), 7.18 (d, J=10.0 Hz, 1H), 2.47 (s, 3H).

Step 2: 5-bromo-4-fluoro-2-methylbenzenesulfonamide

To a saturated solution of NH₃ in THF (60 mL) was added a solution ofthe title compound from step 1 (6.2 g, 21.56 mmol) in THF (20 mL)dropwise at 0° C. The reaction was stirred at 0° C. for 1 hr. Themixture was poured into ice-water (60 mL) and extracted with EA (30mL×3). The organic layer was dried, filtered and concentrated to givethe title compound (5.5 g, 95%) as an off-white solid which was useddirectly without further purification. ¹H NMR (DMSO-d6, 400 MHz): δ 8.05(d, J=7.2 Hz, 1H), 7.59 (s, 2H), 7.47 (d, J=9.6 Hz, 1H), 2.55 (s, 3H).

Step 3: 5-bromo-2-(bromomethyl)-4-fluorobenzenesulfonamide

A mixture of the title compound from step 2 (11 g, 41.03 mmol), BPO(1.36 g, 5.59 mmol) and NBS (14.6 g, 82.06 mmol) in CCl₄ (200 mL) wasstirred at 80° C. for 12 hr under N₂. The mixture was concentrated andthe residue was purified by column chromatography on silica gel(PE:EA=5:1) to give the title compound (3.1 g, 22%) as a light yellowsolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.27 (d, J=6.8 Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 4.81 (s, 2H).

Step 4: 6-bromo-5-fluoro-2,3-dihydro-1,2-benzothiazole 1,1-dioxide

A mixture of the title compound from step 3 (3.1 g, 8.93 mmol) andNaHCO₃ (2.25 g, 26.80 mmol) in CH₃CN (300 mL) was stirred at 80° C. for12 hr. H₂O (100 mL) was added and the mixture was extracted with EA (50mL×2). The organic layer was dried, filtered and concentrated. Theresidue was purified by column chromatography on silica gel (PE:EA=5:1)to give the title compound (1.8 g, 76%) as a light yellow solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.97 (d, J=6.0 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 4.44(s, 2H).

Step 5: 6-bromo-5-fluoro-2-methyl-3H-1,2-benzothiazole 1,1-dioxide

To a mixture of the title compound from step 4 (300 mg, 1.13 mmol) andMeI (240 mg, 1.69 mmol) in CH₃CN (3 mL) was added K₂CO₃ (311 mg, 2.25mmol). The mixture was stirred at 20° C. for 12 hr. The mixture was thenpoured over water (10 mL) and extracted with EA (10 mL×2). The organiclayer was dried and concentrated to give the title compound (300 mg,96%) as a solid which was used directly without further purification.LCMS: 279.9 [M+H]⁺.

Step 6: 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole 1,1-dioxide

A mixture of the title compound from step 5 (300 mg, 1.07 mmol) andCH₃ONa (168 mg, 3.12 mmol) in MeOH (6 mL) was stirred at 60° C. for 8hr. The mixture was concentrated and the residue was purified by columnchromatography on silica gel (PE:EA=2:1) to give the title compound (140mg, 46%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.97 (s, 1H), 6.82(s, 1H), 4.27 (s, 2H), 3.97 (s, 3H), 2.94 (s, 3H). LCMS: 291.9 [M+H]⁺.

Step 7:5-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)-1,3-dimethylpyridin-2-one

A mixture of the title compound of step 6 (40 mg, 0.137 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(41 mg, 0.164 mmol), Pd(dppf)Cl₂ (10 mg, 0.014 mmol) and K₃PO₄ (73 mg,0.343 mmol) in dioxane/H₂O (4/0.4 mL) was stirred at 80° C. for 12 hrunder N₂. The mixture was concentrated and the residue was purified bycolumn chromatography on silica gel (PE:EA=2:1) to give a yellow solidwhich was further purified by prep-HPLC to afford the title compound(20.2 mg, 44%). ¹H NMR (CDCl₃, 400 MHz): δ 7.64 (s, 1H), 7.40-7.38 (m,2H), 6.87 (s, 1H), 4.34 (s, 2H), 3.92 (s, 3H), 3.61 (s, 3H), 2.96 (s,3H), 2.21 (s, 3H). LCMS: 335.1 [M+H]⁺.

Example 44-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 3 bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 7. ¹H NMR (CDCl₃, 400 MHz): δ 8.52-8.50 (m, 1H), 7.71 (s, 1H),7.56-7.51 (m, 2H), 7.07 (d, J=6.8 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H),4.41 (s, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 2.99 (s, 3H). LCMS: 371.1[M+H]⁺.

Example 55-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-oneStep 1: 6-bromo-5-(cyclopropylmethoxy)-2-methyl-3H-1,2-benzothiazole1,1-dioxide

To a solution of cyclopropylmethanol (159 mg, 2.21 mmol) in THF (4 mL)was added NaH (66 mg, 1.66 mmol, 60% in mineral oil) under N₂ at 0° C.The mixture was stirred at 0° C. for 30 min and then a solution of thetitle compound from Example 3, step 5 (300 mg, 1.07 mmol) in THF (2 mL),was added. The reaction was stirred at 60° C. for 5 hr. The mixture wasquenched with H₂O (5 mL) and extracted with EtOAc (5 mL×2). The combinedorganic layers were dried, filtered and concentrated. The residue waspurified by column chromatography on silica gel (PE:EA=4:1) to give thetitle compound (160 mg, 45%). 1H NMR (CDCl3, 400 MHz): δ 7.97 (s, 1H),7.77 (s, 1H), 4.24 (s, 2H), 3.95 (d, J=6.4 Hz, 2H), 2.93 (s, 3H),1.37-1.32 (m, 1H), 0.72-0.68 (m, 2H), 0.45-0.08 (m, 2H). LCMS: 332.0[M+H]⁺.

Step 2:5-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 1, step2, by substituting6-bromo-5-(cyclopropylmethoxy)-2-methyl-3H-1,2-benzothiazole 1,1-dioxidefor 6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (DMSO-d6, 400 MHz): δ 7.88 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H),7.24 (s, 1H), 4.34 (s, 2H), 3.98 (d, J=6.8 Hz, 1H), 3.50 (s, 3H), 2.80(s, 3H), 2.05 (s, 3H), 1.24 (m, 1H), 0.57 (m, 2H), 0.36 (m, 2H). LCMS:375.1 [M+H]⁺.

Example 64-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 1, step2, by substituting6-bromo-5-(cyclopropylmethoxy)-2-methyl-3H-1,2-benzothiazole 1,1-dioxidefor 6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide. 1H NMR (DMSO-d6,400 MHz): δ 8.29 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.52 (m,2H), 7.34 (s, 1H), 7.12 (d, J=8.2 Hz, 1H), 4.42 (s, 2H), 3.95 (m, 1H),3.89 (m, 1H), 3.56 (s, 3H), 2.82 (s, 3H), 0.94 (m, 1H), 0.35 (m, 1H),0.26 (m, 1H), 0.06 (m, 2H). LCMS: 411.1 [M+H]⁺.

Example 74-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-oneStep 1: 6-bromo-5-(cyclopropylmethoxy)-2-ethyl-3H-1,2-benzothiazole1,1-dioxide

The title compound was prepared in a manner similar to Example 5, step1, by substituting ethyl iodide for methyl iodide in the synthesis ofthe Example 3, step 5, precursor. ¹H NMR (CDCl3, 400 MHz): δ 7.96 (s,1H), 6.78 (s, 1H), 4.27 (s, 2H), 3.96 (s, 1H), 3.94 (s, 1H), 3.54 (q,J=7.2 Hz, 2H), 1.39-1.31 (m, 4H), 0.71-0.69 (m, 2H), 0.44-0.07 (m, 2H).

Step 2:4-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 4 bysubstituting 6-bromo-5-(cyclopropylmethoxy)-2-ethyl-3H-1,2-benzothiazole1,1-dioxide for 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole1,1-dioxide. ¹H NMR (CDCl₃, 400 MHz): δ 8.51 (d, J=7.6 Hz, 1H), 7.72 (s,1H), 7.57-7.49 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 6.90 (s,1H), 4.40 (s, 2H), 3.87-3.81 (m, 2H), 3.67 (s, 3H), 3.40 (q, J=7.2 Hz,2H), 1.42 (t, J=7.2 Hz, 3H), 0.98-0.95 (m, 1H), 0.44-0.35 (m, 2H),0.90-0.70 (m, 2H). LCMS: 425.2 [M+H]⁺.

Example 85-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 3 bysubstituting 6-bromo-5-(cyclopropylmethoxy)-2-ethyl-3H-1,2-benzothiazole1,1-dioxide for 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole1,1-dioxide in step 7. 1H NMR (CDCl3, 400 MHz): δ 7.66 (s, 1H), 7.50 (s,2H), 6.82 (s, 1H), 4.33 (s, 2H), 3.91 (d, J=6.8 Hz, 2H), 3.62 (s, 3H),3.37 (q, J=7.2 Hz, 2H), 2.22 (s, 3H), 1.39 (t, J=7.2 Hz, 3H), 1.28-1.25(m, 1H), 0.70-0.65 (m, 2H), 0.37-0.34 (m, 2H). LCMS: 389.1 [M+H]⁺.

Example 91,3-dimethyl-5-[2-methyl-1,1-dioxo-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazol-6-yl]pyridin-2-oneStep 1: 6-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazole1,1-dioxide

To a solution of 6-bromo-5-fluoro-2-methyl-3H-1,2-benzothiazole1,1-dioxide (290 mg, 1.04 mmol) and 2,2,2-trifluoroethanol (320 mg, 3.2mmol) in DMF (10 mL) was added K₂CO₃ (717 mg, 5.2 mmol). The mixture wasstirred at 60° C. for 4 hr. The mixture was cooled, poured over water(10 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound that wasused for the next step without further purification. ¹H NMR (CDCl3, 400MHz) δ 8.03 (s, 1H), 6.87 (s, 1H), 4.51-4.45 (m, 2H), 4.28 (s, 2H), 2.95(s, 3H), 2.89 (s, 3H).

LCMS: 361.8 (M+1)⁺.

Step 2:1,3-dimethyl-5-[2-methyl-1,1-dioxo-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazol-6-yl]pyridin-2-one

The title compound was prepared in a manner similar to Example 3 bysubstituting6-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazole1,1-dioxide for 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole1,1-dioxide in step 7. ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (s, 1H), 7.46 (d,J=2.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 6.87 (s, 1H), 4.34 (q, J=8.0 Hz,2H), 4.35 (s, 2H), 3.62 (s, 3H), 2.97 (s, 3H), 2.21 (s, 3H). LCMS: 403.1[M+H]⁺.

Example 102-methyl-4-[2-methyl-1,1-dioxo-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazol-6-yl]isoquinolin-1-one

The title compound was prepared in a manner similar to Example 4 bysubstituting6-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3H-1,2-benzothiazole1,1-dioxide for 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole1,1-dioxide. ¹H NMR (CDCl₃, 400 MHz): δ 8.53-8.51 (m, 1H), 7.80 (s, 1H),7.58-7.52 (m, 2H), 7.11-7.07 (m, 2H), 6.97 (s, 1H), 4.41 (s, 2H), 4.34(q, J=8.0 Hz, 2H), 3.66 (s, 3H), 3.00 (s, 3H). LCMS: 439.1 [M+H]⁺.

Example 115-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-oneStep 1: 6-bromo-5-(2,4-difluorophenoxy)-2-methyl-3H-1,2-benzothiazole1,1-dioxide

The title compound was prepared in a manner similar to Example 9, step1, by substituting 2,4-difluorophenol for 2,2,2-trifluoroethanol. ¹H NMR(CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.20-7.14 (m, 1H), 7.06-6.94 (m, 2H),6.61 (s, 1H), 4.17 (s, 2H), 2.92 (s, 3H).

LCMS: 391.8 (M+1)⁺.

Step 2:5-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 3 bysubstituting6-bromo-5-(2,4-difluorophenoxy)-2-methyl-3H-1,2-benzothiazole1,1-dioxide for 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole1,1-dioxide in step 7. ¹H NMR (CDCl₃, 400 MHz): δ 7.76 (s, 1H), 7.50 (s,2H), 7.11-6.95 (m, 3H), 6.95 (s, 1H), 4.24 (s, 2H), 3.63 (s, 3H), 2.94(s, 3H), 2.21 (s, 3H). LCMS: 433.1 [M+H]⁺.

Example 125-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 11 bysubstituting1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 2. ¹H NMR (CDCl₃, 400 MHz): δ 7.77 (s, 1H), 7.64 (dd, J₁=9.6 Hz,J₂=2.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.12-7.10 (m, 1H), 7.08-7.05 (m,1H), 7.03-6.96 (m, 1H), 6.66-6.64 (m, 2H), 4.24 (s, 2H), 3.63 (s, 3H),2.94 (s, 3H). LCMS: 419.0 [M+H]⁺.

Example 134-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-oneStep 1: 1-(5-nitro-2,3-dihydroindol-1-yl)ethanone

To a solution of 1-(2,3-dihydroindol-1-yl)ethanone (20 g, 124.07 mmol)in TFA (400 mL) was added a solution of KNO₃ (12.54 g, 124.07 mmol, 1.00Eq) in TFA (50 mL) drop-wise at 5-10° C. during 1 hr. The mixture wasstirred for 3 hr at the same temperature. The reaction mixture waspoured over ice-water (500 ml) and filtered. The residue was washed withEtOH (100 ml) to provide the title compound (18 g, 70% yield) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.31 (d, J=8.8 Hz, 1H), 8.14 (m,1H), 8.05 (s, 1H), 4.20 (t, 2H), 3.30 (t, 2H), 2.29 (s, 3H).

Step 2: 1-(5-amino-2,3-dihydroindol-1-yl)ethanone

To a solution of the title compound from step 1 (18 g, 87.29 mmol) iniPrOH (300 mL) was added Pd/C (1.50 g, 87.29 mmol). The suspension wasdegassed by carrying out three cycles of vacuum followed by nitrogenfilling. The mixture was stirred for 12 hr at 25° C. The catalyst wasremoved by filtration and the filtrate was concentrated under reducedpressure to provide the title compound (15 g, 97% yield) as a yellowsolid which was used directly in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 8.01 (d, J=8.4 Hz, 1H),6.52-6.56 (m, 2H), 4.01 (t, J=8.0 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H),3.0-3.5 (br s, 2H), 2.20 (s, 3H).

Step 3: 1-(5-hydroxy-2,3-dihydroindol-1-yl)ethanone

To a solution of the title compound from step 2 (13.5 g, 76.70 mmol) inH₂SO₄ (100 mL) was added slowly a solution of NaNO₂ (6.35 g, 92.02 mmol)in water (30 mL) at 5-10° C. After the addition was completed, thereaction contents were stirred at the same temperature for 1 hr. Thenthe mixture was poured over a solution of Cu₂O (38.39 g, 268.46 mmol) in30% H₂SO₄ (100 mL) warmed up to 100° C. It was stirred for 1 hr at thattemperature. The mixture was cooled to 25° C. and extracted with EtOAc(200 mL×3). The combined organic layers were washed with brine,filtered, dried over Na₂SO₄, and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography toprovide 5.3 g of crude product as a brown solid. Trituration withacetone (100 mL) afforded pure title compound (3.00 g, 22% yield). ¹HNMR (DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 6.63 (s,1H), 6.50-6.52 (m, 1H), 4.02 (t, J=8.8 Hz, 2H), 3.05 (t, J=8.8 Hz, 2H),2.09 (s, 3H). LCMS: 178.0 [M+H]⁺.

Step 4: 1-(6-bromo-5-hydroxy-2,3-dihydroindol-1-yl)ethanone

To a solution of the title compound from step 3 (3.0 g, 16.95 mmol) inAcOH (25 mL) was added a solution of NBS (3.01 g, 16.95 mmol) in AcOH(25 mL) slowly at 10° C.-20° C. The mixture was stirred at thattemperature for 1 hr. It was then poured over water (50 ml) andextracted with CH₂Cl₂ (200 ml×5). The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (PE:EA=10:1˜1:1) toprovide the title compound (1.10 g, 25% yield) as a solid. ¹H NMR(DMSO-d6, 400 MHz) δ 9.90 (s, 1H), 8.14 (s, 1H), 6.83 (s, 1H), 4.05 (t,J=8.4 Hz, 2H), 3.04 (t, J=8.4 Hz, 2H), 2.11 (s, 3H). LCMS: 256.0, 258.0[M+H]⁺.

Step 5: 1-[6-bromo-5-(cyclopropylmethoxy)-2,3-dihydroindol-1-yl]ethanone

To a solution of the title compound from step 4 (1.0 g, 4.0 mmol) inCH₃CN (20 mL) was added K₂CO₃ (830 mg, 6.0 mmol). The mixture wasstirred for 30 mins. Bromomethylcyclopropane (630 mg, 4.8 mmol) wasadded and reaction was stirred at 70° C. for 6.5 hr. The mixture waspoured over water (50 ml) and extracted with EtOAc (50 ml×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography (PE:EA=10:1˜3:1) to provide the titlecompound (900 mg, 75% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz)δ 8.41 (s, 1H), 6.76 (s, 1H), 4.06 (t, J=8.4 Hz, 2H), 3.84 (d, J=6.8 Hz,2H), 3.13 (t, J=8.4 Hz, 2H), 2.20 (s, 3H), 1.26-1.31 (m, 1H), 0.61-0.66(m, 2H), 0.4 (s, 2H).

LCMS: 310.0; 312.0 [M+H]⁺.

Step 6: 6-bromo-5-(cyclopropylmethoxy)-2,3-dihydro-1H-indole

A solution of the title compound from step 5 (700 mg, 2.26 mmol) in 5 NHCl (70 mL) and MeOH (100 mL) was stirred at 70° C. The startingmaterial was consumed after 4 hr. The pH of the reaction mixture wasadjusted to 8-9 by addition of NaHCO₃. It was then extracted with EtOAc(100 ml×3). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (PE:EA=10:1˜1:1) to afford the title compound (320mg, 53% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.24 (s, 1H), 6.83 (s, 1H),3.83 (d, J=6.8 Hz, 2H), 3.72 (m, 2H), 3.10 (t, J=7.2 Hz, 2H), 1.27 (m,1H), 0.64 (d, J=6.8 Hz, 2H), 0.39 (d, J=4.0 Hz, 2H). LCMS: 268.0; 270.0[M+H]⁺.

Step 7:6-bromo-5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindole

To a solution of the title compound from step 6 (120 mg, 447.5 μmol) inpyridine (5 mL) was added methanesulfonyl chloride (590 mg, 5.15 mmol).The reaction mixture was stirred for 2 hr at RT. It was then poured over1 N HCl (50 ml) and extracted with CH₂Cl₂ (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography toprovide the title compound (120 mg, 77% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.61 (s, 1H), 6.80 (s, 1H), 4.00 (t, J=8.4 Hz, 2H),3.83 (d, J=6.8 Hz, 2H), 3.09 (t, J=8.4 Hz, 2H), 2.86 (s, 3H), 1.29-1.32(m, 1H), 0.64-0.66 (m, 2H), 0.38-0.39 (m, 2H).

Step 8:4-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one

A mixture of the title compound from step 7 (50 mg, 144 umol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(33 mg, 159 umol), Pd(dppf)Cl₂ (5 mg, 7 umol), K₃PO₄ (92 mg, 433 umol)in dioxane (5 mL) and H₂O (0.5 mL) was degassed by performing threecycles of vacuum and N₂ filling. The mixture was stirred for 3 hr at 70°C. It was then cooled down to RT, filtered through Celite andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA=3:1˜1:1) followed by preparative HPLC to providethe title compound (13 mg, 21% yield) as a white solid. ¹H NMR (CDCl₃,400 MHz) δ 8.52 (d, J=7.2 Hz, 1H), 7.49-7.59 (m, 2H), 7.35 (s, 1H),7.24-7.68 (m, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 4.01-4.10 (m, 2H),3.71-3.78 (m, 2H), 3.68 (s, 3H), 3.13-3.25 (m, 2H) 2.90 (s, 3H),0.91-0.97 (m, 1H), 0.37 (brs, 2H), 0.04 (brs, 2H). LCMS: 425.0 [M+H]⁺.

Example 144-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 13 bysubstituting ethanesulfonyl chloride for methanesulfonyl chloride instep 7. ¹H NMR (CDCl₃, 400 MHz) δ 8.50 (d, J=8 Hz, 1H), 7.57 (t, J=8 Hz,1H), 7.50 (t, J=8 Hz, 1H), 7.30 (s, 1H), 7.25 (m, 1H), 7.06 (s, 1 H),6.89 (s, 1H), 4.07-4.12 (m, 2H), 3.70-3.74 (m, 2H), 3.68 (s, 3H), 3.21(t, J=8 Hz, 2H), 3.06-3.12 (q, J=8 Hz, 2H), 1.39 (t, J=8 Hz, 3H), 0.92(m, 1H), 0.35 (m, 2H), 0.02 (m, 2H). LCMS: 439.1 (M+1)⁺.

Example 155-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 13 bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onein step 8. ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (s, 1H), 7.50 (d, J=2 Hz, 1H),7.31 (s, 1H), 6.83 (s, 1H), 4.00 (t, J=8 Hz, 2H), 3.78 (d, J=6 Hz, 2H),3.64 (s, 3H), 3.15 (t, J=8 Hz, 2H), 2.86 (s, 3H), 2.22 (s, 3H),1.16-1.24 (m, 1H), 0.60-0.62 (m, 2H), 0.25-0.30 (m, 2H). LCMS: 389.0(M+1)⁺.

Example 165-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 14 bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (CDCl₃, 400 MHz) δ 7.54 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.82(s, 1H), 4.07 (t, J=8 Hz, 2H), 3.77 (d, J=8 Hz, 2H), 3.63 (s, 3H), 3.15(t, J=8 Hz, 2H), 3.04-3.10 (q, J=8 Hz, 2H), 2.21 (s, 3H), 1.39 (t, J=8Hz, 3H), 1.14-1.20 (m, 1H), 0.58-0.63 (m, 2H), 0.28-0.31 (m, 2H). LCMS:403.0 [M+H]⁺.

Example 17N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol-4-yl]methanesulfonamideStep 1: (E)-2-(4-bromo-2,6-dinitrophenyl)-N,N-dimethylethenamine

A mixture of 5-bromo-2-methyl-1,3-dinitrobenzene (5 g, 19.15 mmol) andBredereck's reagent (10.01 g, 57.45 mmol) was heated at 110° C. for 2hr. The mixture was cooled down to RT and concentrated to give the crudetitle compound (2 g) which was used directly in the next step. ¹H NMR(CDCl₃, 300 MHz) δ 8.34 (s, 2H), 6.50-6.47 (d, 1H, J=10.2 Hz), 5.32˜5.29(d, 1H, J=10.2 Hz), 2.88 (s, 6H). LCMS: 316.0; 318.0 [M+H]⁺.

Step 2: 6-bromo-1H-indol-4-amine

The title compound from step 1 (3 g, 9.49 mmol) was treated with TiCl₃(7.32 g, 47.45 mmol) in a HCl solution (61.20 g, 167.86 mmol). Thereaction mixture was stirred at 25° C. for 16 hr. It was then pouredover 2 N aqueous NaOH (150 mL) and extracted with EtOAc (150 mL). Theorganic phase was dried, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (PE toPE/EA=5/1) to give the title compound (2 g, 36%) as a gray solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.10 (br s, 1H), 7.09˜7.08 (m, 1H), 7.02 (d, J=1.4Hz, 1H), 6.54 (d, J=1.4 Hz, 1H), 6.44˜6.43 (m, 1H), 3.98 (br s, 2H).

Step 3: 1-benzyl-6-bromoindol-4-amine

To a solution of the title compound from step 2 (50 mg, 237 μmol) in DMF(1 mL) was added NaH (6 mg, 250 μmol) at 0° C. The reaction mixture wasstirred at 0° C. for 30 mins. Benzyl bromide (41 mg, 237 umol) was thenadded. The mixture was stirred at 25° C. for 1 hr. Water (2 mL) wasadded and the mixture was extracted with EtOAc (5 mL). The organic layerwas dried, filtered and concentrated under reduced pressure. The residuewas purified by preparative TLC to give the title compound (30 mg, 42%)as a gray solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.33˜7.27 (m, 3H), 7.01˜7.08(d, J=6.8 Hz, 2H), 6.99˜6.98 (m, 1H), 6.91 (s, 1H), 6.53 (s, 1H),6.43˜6.42 (m, 1H), 5.22 (s, 2H). LCMS: 301.0; 303.0 [M+H]⁺.

Step 4: N-(1-benzyl-6-bromoindol-4-yl)methanesulfonamide

To a solution of the title compound from step 3 (30 mg, 99.6 umol) inpyridine (1 mL) at 25° C. was added MsCl (11.41 mg, 99.6 umol) in oneportion. Then the reaction mixture was stirred at 25° C. for 2 hr. Themixture was concentrated under reduced pressure and the residue waspurified by preparative TLC to give the title compound (30 mg, 79%) as asolid. ¹H NMR (CDCl₃, 400 MHz) δ 7.37˜7.32 (m, 5H), 7.14˜7.11 (m, 2H),6.63 (s, 1H), 6.52 (s, 1H), 5.28 (s, 2H), 3.07 (s, 3H). LCMS: 378.8;381.8 [M+H]⁺.

Step 5:N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol-4-yl]methanesulfonamide

To a solution of the title compound from step 4 (50 mg, 131 umol) and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(38 mg, 131 umol) in dioxane (20 mL) and H₂O (2 mL) was addedPd(dppf)Cl₂ (10 mg, 13.2 μmol) and Na₂CO₃ (28 mg, 263 μmol) in oneportion. The mixture was submitted to two vacuum/nitrogen filling cyclesand then heated at 90° C. for 3 hr. The mixture was then cooled to RTand extracted with EtOAc (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EA=5:1˜1:1) followed by preparative HPLCto afford the title compound (22.5 mg, 37%) as a solid. ¹H NMR (CDCl₃,400 MHz) δ 8.52˜8.53 (d, J=1.6 Hz, 1H), 7.57˜7.48 (m, 3H), 7.37˜7.32 (m,3H), 7.21 (s, 1H), 7.16˜7.14 (m, 2H), 7.09 (s, 1H), 6.72 (s, 1H), 6.62(s, 1H), 5.37 (s, 2H), 3.67 (s, 3H), 3.10 (s, 3H). LCMS: 458.1 (M+1)⁺.

Example 18N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 17 bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onein step 5. ¹H NMR (CDCl₃, 400 MHz) δ 7.51 (s, 1H), 7.39 (s, 1H),7.38˜7.31 (m, 4H), 7.19˜7.12 (m, 4H), 6.55 (s, 1H), 6.54 (s, 1H), 5.38(s, 2H), 3.64 (s, 3H), 3.05 (s, 3H), 2.23 (s, 3H). LCMS: 422.0 (M+1)⁺.

Example 19N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydroindol-4-yl]methanesulfonamideStep 1: N-(1-benzyl-6-bromo-2,3-dihydroindol-4-yl)methanesulfonamide

To a solution of the title compound from step 4 (200 mg, 0.53 mmol) inAcOH (5 mL) at 0° C. was added NaBH₃CN (166 mg, 2.64 mmol) in oneportion. The mixture was then warmed to 25° C. and stirred for 10 hr. Itwas diluted with water (30 mL) and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed by saturated NaHCO₃ (100 mL) andbrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EA=5:1˜2:1) to afford the title compound (120 mg, 59%yield) as a white solid. LCMS: 381.0; 383.0 [M+H]+.

Step 2:N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydroindol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 18 bysubstitutingN-(1-benzyl-6-bromo-2,3-dihydroindol-4-yl)methanesulfonamide forN-(1-benzyl-6-bromoindol-4-yl)methanesulfonamide. ¹H NMR (CDCl₃, 400MHz) δ 7.42˜7.26 (m, 7H), 6.78 (s, 1H), 6.34 (s, 1H), 4.33 (s, 2H), 3.60(s, 3H), 3.45˜3.43 (m, 2H), 3.07 (s, 3H), 3.01˜2.97 (m, 2H), 2.22 (s,3H).

LCMS: 424.1 (M+1)⁺.

Example 20N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-2,3-dihydroindol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 17 bysubstitutingN-(1-benzyl-6-bromo-2,3-dihydroindol-4-yl)methanesulfonamide forN-(1-benzyl-6-bromoindol-4-yl)methanesulfonamide in step 5. ¹H NMR(CDCl₃, 400 MHz) δ 8.51 (s, 1H), 7.58˜7.50 (m, 4H), 7.33˜7.27 (m, 5H),7.05 (s, 1H), 6.75 (s, 1H), 6.39 (s, 1H), 4.30 (s, 2H), 3.64 (s, 3H),3.51 (s, 2H), 3.09˜3.05 (m, 5H). LCMS: 460.1 (M+1)⁺.

Example 215-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3-dimethylpyridin-2-oneStep 1: 2,6-diiodo-4-methylsulfonylphenol

To a solution of 4-methylsulfonylphenol (2.0 g, 11.61 mmol) in an AcOH(30 mL)/H₂O (30 mL) mixture was added KI (4.82 g, 29 mmol), NaCl (1.7 g,29 mmol) and NaIO₄ (6.21 g, 29 mmol) at RT. The reaction was stirred at50° C. for 0.5 hr. It was then diluted with EtOAc (300 mL) and washedwith H₂O (100 mL), Na₂SO₃ (200 mL) and brine (70 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The crude product was triturated with PE/EA=5/1 to give the titlecompound (4.5 g, 91%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.24(s, 2H), 6.32 (s, 1H), 3.07 (s, 3H).

Step 2: 2-ethyl-7-iodo-5-methylsulfonyl-1-benzofuran

To a solution of the title compound from step 1 (1.00 g, 2.36 mmol) inpyridine (10 mL) was added but-1-yne (128 mg, 2.36 mmol) and Cu₂O (135mg, 0.94 mmol) at 25° C. The mixture was stirred at 130° C. for 3 hrunder a nitrogen atmosphere. The reaction was cooled to RT, diluted with1N HCl (200 ml) and extracted with EtOAc (30 mL×2). The combined organiclayers were washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby column chromatography (PE:EA=10:1 to 5:1) to afford the titlecompound (400 mg, 48%) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d,J=1.6 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 3.09 (s, 3H), 2.90(q, J=7.6 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H). LCMS: 350.9 [M+H]⁺.

Step 3:5-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3-dimethylpyridin-2-one

To a solution of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(71 mg, 285.5 umol) and the title compound from step 2 (100 mg, 285μmol) in dioxane (20 mL) and H₂O (2 mL) was added Pd(dppf)Cl₂ (21 mg, 28umol) and Na₂CO₃ (61 mg, 572 μmol). The mixture was submitted to threecycles of vacuum/nitrogen filling and then heated at 90° C. for 4 hr. Itwas then cooled to RT and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography followed bypreparative HPLC to afford the title compound (10 mg, 10%) as a solid.¹H NMR (CDCl₃, 400 MHz) δ 8.03 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.76(s, 1H), 6.57 (s, 1H), 3.69 (s, 3H), 3.12 (s, 3H), 2.90 (q, J=6.8 Hz,2H), 2.28 (s, 3H), 1.40 (t, J=6.8 Hz, 3H). LCMS: 345.9 [M+H]⁺.

Example 22N-[2-(1,5-dimethyl-6-oxopyridin-3-yl)-9-[(4-fluorophenyl)methyl]-8-methylpurin-6-yl]methanesulfonamideStep 1: 2,6-dichloro-9-[(4-fluorophenyl)methyl]-8-methylpurine

A mixture of 2,6-dichloro-8-methyl-9H-purine (100 mg, 0.49 mmol), K₂CO₃(204 mg, 1.5 mmol) and 1-(bromomethyl)-4-fluorobenzene (186 mg, 0.98mmol) in DMF (5 mL) was stirred at RT overnight. The reaction mixturewas diluted with ice water (15 mL) and extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromate-graphy on silica gel (PE:EA=5:1) to give thetitle compound (90 mg, 59%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃):δ 7.21-7.16 (m, 2H), 7.07-7.01 (m, 2H), 5.37 (s, 2H), 2.59 (s, 3H).

Step 2:N-[2-chloro-9-[(4-fluorophenyl)methyl]-8-methylpurin-6-yl]methanesulfonamide

A mixture of the title compound from step 1 (300 mg, 0.97 mmol),MeSO₂NH₂ (93 mg, 0.97 mmol) and Cs₂CO₃ (379 mg, 1.16 mmol) in dioxane(15 mL) was stirred at 115° C. for 8 hr. The reaction mixture was cooledto RT, diluted with water (50 ml) and extracted with DCM (30 ml×3). Thecombined organic layers were washed with brine (30 ml×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas washed with ether (10 ml×2) to afford the title compound (200 mg,56%) as a solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.23-7.16 (m, 4H), 5.27(s, 2H), 3.03 (s, 3H), 2.35 (s, 3H).

Step 3:N-[2-(1,5-dimethyl-6-oxopyridin-3-yl)-9-[(4-fluorophenyl)methyl]-8-methylpurin-6-yl]methanesulfonamide

A mixture of the title compound from step 2 (100 mg, 0.27 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(88 mg, 0.35 mmol), K₂CO₃ (75 mg, 0.54 mmol) and Pd-118 (17 mg, 0.027mmol) in DMA (10 mL) under N₂ was heated to 145° C. for 3 hr. Thereaction was cooled to RT and filtered. The filtrate was diluted withwater, adjusted to pH 3-4 by addition a 2M HCl solution, and extractedwith DCM (20 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified with preparative TLC(DCM: MeOH=20:1) to give the title compound (36 mg, 29%) as a solid. ¹HNMR (300 MHz, DMSO-d₆): δ 8.51 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.1 Hz,1H), 7.34-7.31 (m, 2H), 7.22-7.19 (m, 2H), 5.51 (s, 2H), 3.58 (s, 3H),3.55 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H). LCMS: 457 [M+H].

Example 235-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 21 bysubstituting ethynylcyclopropane for but-1-yne in step 2. ¹H NMR (CDCl₃,400 MHz) δ 7.98 (d, 1H, J=1.6 Hz), 7.87˜7.86 (d, 1H, J=1.6 Hz), 7.79 (d,J=2 Hz, 1H), 7.73 (s, 1H), 6.51 (s, 1H), 3.69 (s, 3H), 3.11 (s, 3H),2.28 (s, 3H), 2.13˜2.11 (m, 1H), 1.15˜1.11 (m, 2H), 1.01˜0.99 (m, 2H).LCMS: 358.0 (M+H⁺).

Example 244-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 23 bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein the Suzuki coupling step. ¹H NMR (MeOD, 400 MHz) δ 8.47˜8.45 (dd,J=2.8 Hz, J=8.4 Hz, 1H), 8.19˜8.18 (d, 1H, J=2.0 Hz), 7.83˜7.82 (d, J=2Hz, 1H), 7.68˜7.65 (d, J=6.4 Hz, 1H), 7.62˜7.60 (m, 2H), 7.23˜7.21 (d,1H, J=8.4 Hz), 6.73 (s, 1H), 3.71 (s, 3H), 3.20 (s, 3H), 2.07˜2.03 (m,1H), 0.98˜0.95 (m, 2H), 0.79˜0.77 (m, 2H). LCMS: 394.0 (M+H⁺).

Example 251,3-dimethyl-5-(5-methylsulfonyl-2-phenyl-1-benzofuran-7-yl)pyridin-2-one

The title compound was prepared in a manner similar to Example 21 bysubstituting ethynylbenzene for but-1-yne in step 2. ¹H NMR (CDCl₃, 400MHz) δ 8.14 (s, 1H), 7.99 (s, 1H), 7.88-7.84 (m, 4H), 7.55-7.46 (m, 3H),7.18 (s, 1H), 3.74 (s, 3H), 3.15 (s, 3H), 2.31 (s, 3H).

LCMS: 394.0 (M+H⁺).

Example 262-methyl-4-(5-methylsulfonyl-2-phenyl-1-benzofuran-7-yl)isoquinolin-1-one

The title compound was prepared in a manner similar to Example 25 bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein the Suzuki coupling step. ¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 1H,J=2.4 Hz), 8.28 (s, 1H), 7.90 (d, 1H, J=1.6 Hz), 7.68 (m, 2H), 7.60-7.58(m, 2H), 7.43-7.36 (m, 5H), 7.21 (s, 1H), 3.73 (s, 3H), 3.18 (s, 3H).LCMS: 430.0 (M+H⁺).

Example 27 N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzotriazol-4-yl]ethanesulfonamide Step 1:6-bromo-4-nitro-1H-benzotriazole

NaNO₂ (937 mg, 13.6 mmol) was added to solution of5-bromo-3-nitrobenzene-1,2-diamine (3.0 g, 12.9 mmol) in AcOH (45 mL).The mixture was stirred for 20 min at RT and for 2.5 hr at 65° C. It wasthen cooled to RT and treated with water (80 mL). The mixture wasextracted with CH₂Cl₂ (100 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was triturated witha PE/EA (15:1, 25 mL) mixture for 10 min. It was then filtered and driedunder vacuum to give the title compound (1.0 g, 32%) as a gray solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.52 (s, 1H), 6.13 (s, 1H).LCMS: 243; 245 (M+H)⁺.

Step 2: 1-benzyl-6-bromo-4-nitrobenzotriazole

A mixture of the title compound from step 1 (500 mg, 2.07 mmol), benzylbromide (530 mg, 3.10 mmol) and K₂CO₃ (570 g, 4.13 mmol) in DMF (8 mL)was stirred at RT overnight. The reaction was diluted with water (40 mL)and extracted with DCM (30 mL×2). The organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (110 mg, 16%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 8.33 (d, J=1.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.39-7.37 (m, 3H),7.29-7.27 (m, 2H), 5.93 (s, 2H).

LCMS: 333; 335 (M+H)⁺.

Step 3: N-(1-benzyl-6-bromobenzotriazol-4-yl)ethanesulfonamide

The title compound from step 2 (110 mg, 0.33 mmol) was suspended in MeOH(9 mL) and saturated NH₄Cl aqueous solution (3 mL) and Fe (92 mg, 1.64mmol) were added. The resulting mixture was heated at 90° C. for 1.5 hr.It was then filtered, treated with water (30 mL) and extracted with DCM(40 mL×2). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was dissolved inDCM (10 mL). Et₃N (67 mg, 0.663 mmol) and ethanesulfonyl chloride (64mg, 0.496 mmol) were added. The mixture was stirred at RT for 2 hr. Thereaction was diluted with water (30 mL) and extracted with DCM (35mL×2). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified withpreparative TLC (DCM as elution solvent) to give the title compound (41mg, 31% for two steps) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.84(s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.29-7.28 (m, 2H),7.23 (d, J=1.8 Hz, 1H), 5.76 (s, 2H), 3.27 (q, J=7.2 Hz, 2H), 1.41 (t,J=7.2 Hz, 3H). LCMS: 395; 397 (M+H)⁺.

Step 4:N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzotriazol-4-yl]ethanesulfonamide

A mixture of the title compound from step 3 (41 mg, 0.104 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(31 mg, 0.125 mmol), K₂CO₃ (43 mg, 0.312 mmol) and Pd(dppf)Cl₂ (7.6 mg,0.010 mmol) in dioxane/H₂O (6 mL/2 mL) was heated to 90° C. for 2 hr. Itwas then cooled to RT and filtered. The filtrate was diluted with water(15 mL) and extracted with DCM (25 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified with preparative TLC (PE/EtOAc 1:1) to give the titlecompound (26 mg, 57%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.73(s, 1H), 7.49 (s, 1H), 7.40-7.35 (m, 5H), 7.31-7.28 (m, 2H), 7.00 (s,1H), 5.84 (s, 2H), 3.62 (s, 3H), 3.25 (q, J=7.2 Hz, 2H), 2.22 (s, 3H),1.43 (t, J=7.2 Hz, 3H). LCMS: 438 (M+H)⁺.

Example 28N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]benzotriazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 27 bysubstituting 1-(bromomethyl)-4-fluorobenzene for benzyl bromide in step2. ¹H NMR (300 MHz, DMSO-d₆) δ 10.4 (s, 1H), 8.02-8.01 (m, 1H), 7.87 (d,J=1.2 Hz, 1H), 7.75-7.74 (m, 1H), 7.48-7.43 (m, 2H), 7.39 (d, J=1.2 Hz,1H), 7.23-7.17 (m, 2H), 5.95 (s, 2H), 3.55 (s, 3H), 3.44-3.37 (m, 2H),2.11 (s, 3H), 1.31 (t, J=7.2 Hz, 3H). LCMS: 456 (M+H)⁺.

Example 294-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-2-methylisoquinolin-1-oneStep 1: methyl 5-bromo-2-fluoro-4-hydroxybenzoate

Br₂ (9.84 g, 61.5 mmol) in AcOH (30 mL) was added to a mixture of methyl2-fluoro-4-hydroxybenzoate (9.50 g, 55.9 mmol) in AcOH (250 mL) at RTand then stirred at RT overnight. Concentrated, the residue wasdissolved in EtOAc (150 mL), washed with H₂O (100 mL), brine (100 mL),dried over Na₂SO₄, filtered, concentrated and purified with columnchromatography on silica gel (PE/EtOAc=50:1 to 20:1 to 10:1) to give thetitle compound (11.5 g, 82%) as a white solid. ¹H NMR (300 MHz, CDCl₃):δ 8.11 (d, J=7.2 Hz, 1H), 6.80 (d, J=11.7 Hz, 1H), 6.13 (s, 1H), 3.90(s, 3H). LCMS: 249, 251 (M+H⁺).

Step 2: methyl 5-bromo-4-(cyclopropylmethoxy)-2-fluorobenzoate

A mixture of the title compound of step 1 (10.0 g, 40.1 mmol),bromomethyl-cyclopropane (10.8 g, 80.0 mmol) and K₂CO₃ (16.6 g, 120mmol) in DMF (150 mL) was warmed at 50° C. overnight. Cooled to RT,filtered, and the filtrate subjected to aqueous extractive work up withDCM (200 mL×2), the organic layer was dried over Na₂SO₄, filtered andconcentrated to give the title compound (11.0 g, 90%) as a white solid.¹H NMR (300 MHz, CDCl₃): δ 8.13 (d, J=7.8 Hz, 1H), 6.60 (d, J=12.3 Hz,1H), 3.91 (d, J=6.9 Hz, 2H), 3.89 (s, 3H), 1.34-1.29 (m, 1H), 0.071-0.65(m, 2H), 0.41-0.37 (m, 2H). LCMS: 303, 305 (M+H⁺).

Step 3: 5-bromo-6-(cyclopropylmethoxy)-1-methyl-2H-indazol-3-one

A mixture of the title compound of step 2 (10.5 g, 34.5 mmol) andmethylhydrazine (12.0 g, 104 mmol, 40% in H₂O) in n-BuOH (100 mL) washeated to 160° C. for 10 hr. After cooling to RT, hexane (130 mL) wasadded. The resulting precipitate was collected, dissolved in EtOAc (100mL), and washed with H₂O (150 mL×2). The organic layer was dried overNa₂SO₄, filtered, and concentrated to give the title compound (5.5 g,53%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.75 (s, 1H), 7.00(s, 1H), 3.94 (d, J=7.2 Hz, 2H), 3.66 (s, 3H), 1.30-1.21 (m, 1H),0.62-0.56 (m, 2H), 0.39-0.34 (m, 2H). LCMS: 297, 299 (M+H⁺).

Step 4: 5-bromo-6-(cyclopropylmethoxy)-1-methyl-3-methylsulfanylindazole

A mixture of the title compound of step 3 (500 mg, 1.68 mmol) andLawesson's reagent (675 mg, 1.68 mmol) in toluene (10 mL) was heated to130° C. for 1.5 hr. After cooling to RT and concentrating, the residuewas dissolved in ACN (25 mL) and Cs₂CO₃ (3.30 g, 10.1 mmol) andiodomethane (1.43 g, 10.0 mmol) were added. The mixture was stirred at30° C. for 18 hr, filtered and the filtrate was purified by prep-TLC(PE/EtOAc=5:1) to give the title compound (170 mg, 31%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃): δ 7.85 (s, 1H), 6.64 (s, 1H), 3.95-3.93(m, 5H), 2.57 (s, 3H), 1.39-1.35 (m, 1H), 0.72-0.66 (m, 2H), 0.47-0.42(m, 2H).

Step 5: 5-bromo-6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazole

A mixture of the title compound of step 4 (120 mg, 0.367 mmol) and oxone(380 mg, 0.618 mmol) in DMF (5 mL) was heated at 50° C. for 7 hr. Aftercooling to RT and quenching with saturated aqueous NaHSO₃ (25 mL), themixture was neutralized with saturated aqueous NaHCO₃ (20 mL) andextracted with DCM (30 mL×2). The combined organics were dried overNa₂SO₄, filtered, and concentrated to give the title compound (120 mg,91%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.31 (s, 1H), 6.72 (s,1H), 4.09 (s, 3H), 3.97 (d, J=6.6 Hz, 2H), 3.24 (s, 3H), 1.42-1.35 (m,1H), 0.75-0.68 (m, 2H), 0.50-0.44 (m, 2H).). LCMS: 359, 361 (M+H⁺).

Step 6:4-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-2-methylisoquinolin-1-one

A mixture of the title compound of step 5 (120 mg, 0.334 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(115 mg, 0.404 mmol), K₂CO₃ (138 mg, 1.0 mmol) and Pd(dppf)Cl₂ (25 mg,0.034 mmol) in dioxane (10 mL) and H₂O (3 mL) was heated to 85° C. for 1hr and then cooled to RT. After DCM (30 mL) aqueous extractive work up,the organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification by prep-TLC (PE/EtOAc=1:1) gave the title compound (21 mg,14%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (d, J=8.0 Hz,1H), 7.81 (s, 1H), 7.63-7.59 (m, 1H), 7.53-7.49 (m, 2H), 7.44 (s, 1H),7.10 (d, J=8.0 Hz, 1H), 4.19 (s, 3H), 4.04-3.99 (m, 1H), 3.90-3.86 (m,1H), 3.58 (s, 3H), 3.33 (s, 3H), 0.98-0.94 (m, 1H), 0.35-0.33 (m, 1H),0.27-0.24 (m, 1H), 0.07-0.03 (m, 2H).

LCMS: 438 (M+H⁺).

Example 304-[6-(cyclopropylmethoxy)-3-ethylsulfonyl-1-methylindazol-5-yl]-2-methylisoquinolin-1-oneStep 1: 5-bromo-6-(cyclopropylmethoxy)-3-ethylsulfanyl-1-methylindazole

A mixture of the title compound of Example 29, step 3 (500 mg, 1.68mmol) and Lawesson's reagent (675 mg, 1.68 mmol) in toluene (10 mL) washeated at 130° C. for 1.5 hr. After cooling to RT and concentrating, theresidue was dissolved in ACN (25 mL). Cs₂CO₃ (3.30 g, 10.1 mmol) andiodoethane (1.58 g, 10.1 mmol) were added. The mixture was stirred at30° C. for 18 hr and filtered. The filtrate was concentrated andpurified by prep-TLC (PE/EtOAc=5:1) to give the title compound (155 mg,27%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.88 (s, 1H), 6.66 (s,1H), 3.97-3.94 (m, 5H), 3.00 (q, J=14.7, 7.2 Hz, 2H), 1.39-1.25 (m, 4H),0.72-0.66 (m, 2H), 0.48-0.42 (m, 2H). LCMS: 341, 343 (M+H⁺).

Step 2: 5-bromo-6-(cyclopropylmethoxy)-3-ethylsulfonyl-1-methylindazole

A mixture of the title compound of step 1(100 mg, 0.294 mmol) and oxone(361 mg, 0.588 mmol) in DMF (5 mL) was heated at 50° C. for 7 hr. Aftercooling to RT and quenching with saturated aqueous NaHSO₃ (25 mL), themixture was neutralized with saturated aqueous NaHCO₃ (20 mL) andextracted with DCM (30 mL×2). The combined organics were dried overNa₂SO₄, filtered, and concentrated to give the title compound (100 mg,92%) as a white solid.

LCMS: 373, 375 (M+H⁺).

Step 3:4-[6-(cyclopropylmethoxy)-3-ethylsulfonyl-1-methylindazol-5-yl]-2-methylisoquinolin-1-one

A mixture of the title compound of step 2 (100 mg, 0.269 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(92 mg, 0.323 mmol), K₂CO₃ (111 mg, 0.804 mmol) and Pd(dppf)Cl₂ (20 mg,0.027 mmol) in dioxane (10 mL) and H₂O (3 mL) was heated at 85° C. for1.5 hr and then cooled to RT. After DCM (30 mL) extractive work up, theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification by prep-TLC (PE/EtOAc 1:1) gave the title compound (35 mg,29%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (d, J=7.6 Hz,1H), 7.75 (s, 1H), 7.58-7.54 (m, 1H), 7.48-7.45 (m, 2H), 7.40 (s, 1H),7.06 (d, J=8.0 Hz, 1H), 4.15 (s, 3H), 3.99-3.95 (m, 1H), 3.86-3.81 (m,1H), 3.53 (s, 3H), 3.35 (q, J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H),0.95-0.89 (m, 1H), 0.31-0.28 (m, 1H), 0.22-0.20 (m, 1H), 0.03-0.00 (m,2H). LCMS: 452 (M+H⁺).

Example 31N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]methanesulfonamideStep 1: 5-bromo-3-nitrobenzene-1,2-diamine

A mixture of 4-bromo-2,6-dinitroaniline (5.5 g, 21.2 mmol) and (NH₄)₂S(10.5 mL, 21.2 mmol) in ethanol (150 mL) was heated at 90° C. for 1 hr.TLC showed incomplete consumption of starting material. Additional(NH₄)₂S (10.5 mL, 21.2 mmol) was added, and the reaction was stirred at90° C. for 1 hr more. The mixture was concentrated and purified onsilica gel (PE/DCM=1:1) to give the title compound (2.5 g, 51%) as a redsolid. LCMS: 230, 232 (M−H⁻).

Step 2: 6-bromo-4-nitro-1H-benzimidazole

To a suspension of the title compound of step 1(500 mg, 2.2 mmol) in 4 MHCl (5 mL, 17 mmol) was added formic acid (230 mg, 4.4 mmol). Themixture was heated at 120° C. for 1.5 hr, and then cooled to RT. Waterwas added and neutralization with concentrated NH₄OH gave a precipitatewhich was collected, washed with water, and dried to give the titlecompound (510 mg, 97%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ11.0 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.39 (d, J=1.6 Hz, 1H). LCMS: 240,242 (M−H⁻).

Step 3: 1-benzyl-6-bromo-4-nitrobenzimidazole

A mixture of the title compound of step 2 (400 mg, 1.57 mmol), K₂CO₃(325 mg, 2.36 mmol) and bromomethylbenzene (322 mg, 1.88 mmol) in DMF (5mL) was stirred at RT overnight. The mixture was partitioned betweenwater (20 mL) and EtOAc (20 mL), extracted with EtOAc (50 mL×2) whichwas then washed with brine, dried over Na₂SO₄, concentrated, andpurified by column chromatography on silica gel (DCM) to give the titlecompound (480 mg, 89%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.62 (br s, 1H), 8.31 (d, J=1.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H),7.40-7.28 (m, 3H), 7.14 (d, J=7.2 Hz, 2H), 5.62 (s, 2H).

Step 4: 1-benzyl-6-bromobenzimidazol-4-amine

A mixture of the title compound of step 3 (320 mg, 0.97 mmol), vanadylacetylacetonate (11 mg, 3%) and Pt/C (33 mg, 10%) in THF (10 mL) underH₂ was stirred at RT overnight. The insoluble components were removed byfiltration, washing with THF, and the combined filtrate/washes wereconcentrated and purified by column chromatography on silica gel (DCM)to give the title compound (260 mg, 90%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.35-7.23 (m, 5H), 6.81 (d, J=2.0 Hz,1H), 6.46 (d, J=2.4 Hz, 1H), 5.61 (br s, 2H), 5.36 (s, 2H).). LCMS: 302,304 (M+H⁺).

Step 5: N-(1-benzyl-6-bromobenzimidazol-4-yl)methanesulfonamide

The title compound of step 4 (325 mg, 1.08 mmol) was dissolved in DCM(10 mL) at 0° C. and TEA (1.1 g, 10.7 mmol) was added followed by MsCl(616 mg, 5.4 mmol). The mixture was warmed to RT and stirred for 3 hr.The mixture was poured into ice-water and extracted with DCM (50 mL),dried over Na₂SO₄, filtered, and concentrated. The residue(di-sulfonylated product) (500 mg) was suspended in THF (10 mL) and 3MNaOH (2 mL) was added. The mixture was heated at 45° C. for 0.5 hr.After cooling to RT, addition of water, and EtOAc extractive work up (50mL*2), the combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the title compound (350 mg, 86%) as a yellow solid.LCMS: 380, 382 (M+H⁺).

Step 6:N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]methanesulfonamide

A mixture of the title compound of step 5 (100 mg, 0.26 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(79 mg, 0.32 mmol), K₂CO₃ (108 mg, 0.78 mmol) and Pd(dppf)Cl₂ (19 mg,0.026 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ was heated at 85° C. for2 hr. Cooled to RT and filtered, the filtrate was partitioned betweenwater and EtOAc (50 mL), and the organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography on silica gel (PE/EtOAc=5:1 to 2:1) to give the titlecompound (19 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.66 (s, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.62 (s, 1H),7.41-7.39 (m, 1H), 7.26-7.13 (m, 5H), 5.56 (s, 2H), 3.53 (s, 3H), 3.23(s, 3H), 2.10 (s, 3H). LCMS: 423 (M+H⁺).

Example 32N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole

A mixture of the title compound of Example 31, step 2 (1.1 g, 4.56mmol), K₂CO₃ (944 mg, 6.84 mmol) and 3-(bromomethyl)-1-fluorobenzene(1.04 g, 5.48 mmol) in DMF (15 mL) was stirred at RT overnight. Themixture was diluted with water (50 mL) and EtOAc (30 mL), and extractedwith EtOAc (50 mL*2). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated, and purified by columnchromatography on silica gel (DCM) to give the title compound (1.1 g,69%) as a red solid. LCMS: 350, 352 (M+H⁺).

Step 2: 6-bromo-1-[(3-fluorophenyl)methyl]benzimidazol-4-amine

The title compound of step 1 (1.1 g, 3.14 mmol) was suspended in MeOH(18 mL) and saturated aqueous NH₄Cl (6 mL) and Fe (880 mg, 15.7 mmol)were added. The mixture was heated to 85° C. for 1 hr, filtered, and thefiltrate partitioned between water and DCM (40 mL×2). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive the title compound (850 mg, 85%) as a yellow solid. LCMS: 320, 322(M+H⁺).

Step 3:N-[6-bromo-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]methanesulfonamide

The title compound of step 2 (400 mg, 1.25 mmol) was dissolved in DCM(10 mL) at 0° C., TEA (1.26 g, 12.5 mmol) followed by methanesulfonylchloride (713 mg, 6.25 mmol) were added. The mixture was warmed to RTand stirred for 3 hr. The mixture was poured into ice water andextracted with DCM (50 mL), dried over Na₂SO₄, filtered, andconcentrated. The residue (di-sulfonylated product) (700 mg) wassuspended in THF (10 mL) and 3M NaOH (2 mL) was added. The mixture washeated at 45° C. for 0.5 hr. After cooling to RT, addition of water, andEtOAc extractive work up (50 mL×2), the combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the title compound(300 mg, 60%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.90 (s,1H), 8.48 (s, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.43-7.37 (m, 1H), 7.24 (d,J=1.6 Hz, 1H), 7.23-7.20 (m, 1H), 7.16-7.11 (m, 2H), 5.52 (s, 2H), 3.24(s, 3H).

LCMS: 398, 400 (M+H⁺).

Step 4:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]methanesulfonamide

A mixture of the title compound of step 3 (100 mg, 0.25 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(75 mg, 0.30 mmol), K₂CO₃ (104 mg, 0.75 mmol) and Pd(dppf)Cl₂ (19.0 mg,0.025 mmol) in dioxane/H₂O (9 mL/3 mL) was heated at 85° C. for 2 hr.After filtering, the filtrate was partitioned between EtOAc (25 mL) andwater. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification by prep-TLC (EtOAc) gave the title compound(19 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s,1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.42-7.37(m, 1H), 7.25-7.10 (m, 4H), 5.55 (s, 2H), 3.53 (s, 3H), 3.23 (s, 3H),2.10 (s, 3H). LCMS: 441 (M+H⁺).

Example 33N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]ethanesulfonamideStep 1:N-[6-bromo-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]ethanesulfonamide

The title compound of Example 32, step 2 (450 mg, 1.41 mmol) wasdissolved in DCM (10 mL) at 0° C. and triethylamine (1.42 g, 14.1 mmol)followed by ethanesulfonyl chloride (906 mg, 7.05 mmol) were added. Themixture was stirred at RT for 3 hr, poured into ice water, extractedwith DCM (50 mL×3), dried over Na₂SO₄, filtered and concentrated. Theresidue (di-sulfonylated product) was suspended in THF (10 mL) and 3MNaOH solution (2.5 mL) was added. The mixture was heated at 45° C. for0.5 hr. After cooling to RT, addition of water and EtOAc extractive workup (50 mL×2), the combined organic layers were dried over Na₂SO₄,filtered and concentrated to give the title compound (410 mg, 71%) as ayellow solid. LCMS: 412, 414 (M+H⁺).

Step 2:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]ethanesulfonamide

A mixture of the title compound of step 1 (150 mg, 0.36 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(108 mg, 0.44 mmol), K₂CO₃ (149 mg, 1.08 mmol) and Pd(dppf)Cl₂ (26.0 mg,0.036 mmol) in dioxane/H₂O (12 mL/4 mL) was heated at 85° C. for 2 hr.After filtering, the filtrate was partitioned between EtOAc and water.After EtOAc extractive work up (25 mL*3), the organic layer was driedover Na₂SO₄, filtered, concentrated, and purified by prep-TLC (EtOAc) togive the title compound (28 mg, 17%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): 6.9.64 (s, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.62(s, 1H), 7.41-7.38 (m, 1H), 7.28 (s, 1H), 7.24-7.11 (m, 3H), 5.55 (s,2H), 3.53 (s, 3H), 3.35-3.29 (m, 2H), 2.10 (s, 3H), 1.30 (t, J=7.6 Hz,3H). LCMS: 455 (M+H⁺).

Example 34N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-2-methyl-4-nitro-1H-benzimidazole

To a suspension of the title compound of Example 31, step 1 (500 mg, 2.2mmol) in 5 M HCl (1.1 mL, 5.5 mmol) was added pentane-2,4-dione (230 mg,4.4 mmol). The reaction mixture was heated at 120° C. for 1.5 hr. Aftercooling, water was added, and the mixture was neutralized withconcentrated NH₄OH. The precipitate was collected, washed with water,and dried to give the title compound (540 mg, 97%) as a yellow solid.LCMS: 255, 257 (M+H⁺).

Step 2:N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound of step 1 was substituted for the title compound ofExample 31, step 2 in Example 31, step 3. A four step synthesis wascarried out in a similar manner as Example 31, steps 3-6 to give thetitle compound (25 mg, 10% for 4 steps) as a white solid. ¹H NMR (400MHz, DMSO-d₆): δ 9.59 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.69 (s, 1H),7.57 (d, J=0.8 Hz, 1H), 7.36-7.26 (m, 3H), 7.23 (d, J=1.2 Hz, 1H), 7.14(d, J=7.2 Hz, 2H), 5.53 (s, 2H), 3.52 (s, 3H), 3.21 (s, 3H), 2.5 (s,3H), 2.08 (s, 3H). LCMS: 437 (M+H⁺).

Example 35N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-1-[(3-fluorophenyl)methyl]-2-methyl-4-nitrobenzimidazole

A mixture of the title compound of Example 34, step 1 (700 mg, 2.75mmol), K₂CO₃ (570 mg, 4.13 mmol) and 3-(bromomethyl)-1-fluorobenzene(627 mg, 3.3 mmol) in DMF (10 mL) was stirred at RT overnight. Thereaction mixture was diluted with water (50 mL) and EtOAc (30 mL) andextracted with EtOAc (50 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated and purified by columnchromatography on silica gel (DCM) to give the title compound (350 mg,35%) as a red solid. LCMS: 364, 366 (M+H⁺).

Step 2:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound of step 1 was substituted for the title compound ofExample 32, step 1 in Example 32, step 2. A three step synthesis wascarried out in a similar manner as Example 32, steps 2-4 to give thetitle compound (19 mg, 10% for 3 steps) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ. 9.59 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.69 (s, 1H),7.57 (s, 1H), 7.41-7.36 (m, 1H), 7.24 (s, 1H), 7.15-7.10 (m, 1H), 7.00(d, J=10.0 Hz, 1H), 5.55 (s, 2H), 3.52 (s, 3H), 3.22 (s, 3H), 2.50 (s,3H), 2.08 (s, 3H). LCMS: 455 (M+H⁺).

Example 36N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]ethanesulfonamide

The title compound (26 mg) was prepared in a similar manner to Example35 except that ethanesulfonyl chloride was substituted formethanesulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆): 6.9.57 (s, 1H),7.87 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.41-7.36(m, 1H), 7.25 (d, J=0.8 Hz, 1H), 7.15-7.10 (m, 1H), 6.98 (d, J=5.6 Hz,1H), 6.91 (d, J=7.6 Hz, 1H), 5.54 (s, 2H), 3.52 (s, 3H), 3.31-3.27 (m,2H), 2.50 (s, 3H), 2.00 (s, 3H), 1.30 (t, J=7.2 Hz, 3H). LCMS: 469(M+H⁺).

Example 37N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-1-[(4-fluorophenyl)methyl]-2-methyl-4-nitrobenzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting 6-bromo-2-methyl-4-nitro-1H-benzimidazole for6-bromo-4-nitro-1H-benzimidazole and 1-(bromomethyl)-4-fluorobenzene forbromomethylbenzene. LCMS: 364; 366 (M+H⁺).

Step 2:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 32, steps2 through 4, by substituting6-bromo-1-[(4-fluorophenyl)methyl]-2-methyl-4-nitrobenzimidazole for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole in step 2. ¹HNMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.70-7.69(m, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.23-7.14 (m, 5H), 5.51 (s, 2H), 3.53(s, 3H), 3.22 (s, 3H), 2.50 (s, 3H), 2.09 (s, 3H). LCMS: 455 (M+H⁺).

Example 38N-[1-[(4-fluorophenyl)methyl]-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 37 bysubstituting3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein the Suzuki coupling step. ¹H NMR (400 MHz, CDCl3): δ 7.48 (s, 1H),7.10-7.03 (m, 5H), 6.99 (s, 1H), 6.81 (s, 1H), 5.34 (s, 2H), 3.87 (s,3H), 3.63 (s, 3H), 3.08 (s, 3H), 2.59 (s, 3H). LCMS: 471 (M+H⁺).

Example 39N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-1-(cyclopropylmethyl)-2-methyl-4-nitrobenzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting 6-bromo-2-methyl-4-nitro-1H-benzimidazole for6-bromo-4-nitro-1H-benzimidazole and bromomethylcyclopropane forbromomethylbenzene. ¹H NMR (300 MHz, CDCl₃): δ 8.21 (s, 1H), 7.75 (s,1H), 4.05 (d, J=6.9 Hz, 2H), 2.73 (s, 3H), 1.25-1.19 (m, 1H), 0.71-0.65(m, 2H), 0.43-0.37 (m, 2H).

Step 2:N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 32, steps2 through 4, by substituting6-bromo-1-(cyclopropylmethyl)-2-methyl-4-nitrobenzimidazole for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole in step 2. ¹HNMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.46 (s, 1H), 7.42 (s 1H), 7.11(s, 1H), 4.05 (d, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.07 (s, 3H), 2.66 (s,3H), 2.25 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.0.66 (m, 2H), 0.44-0.42 (m,2H). LCMS: 401 (M+H⁺).

Example 40 N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide Step 1:6-bromo-1-butyl-4-nitrobenzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting 1-bromobutane for bromomethylbenzene. ¹H NMR (300MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.16 (d, J=1.6 Hz,1H), 4.35 (t, J=7.2 Hz, 2H), 1.83-1.73 (m, 2H), 1.32-1.20 (m, 2H), 0.90(t, J=7.2 Hz, 3H).

Step 2: N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 32, steps2 through 4, by substituting 6-bromo-1-butyl-4-nitrobenzimidazole for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole in step 2 andethanesulfonyl chloride for methanesulfonyl chloride in step 3. ¹H NMR(300 MHz, DMSO-d₆): δ 9.60 (s, 1H), 8.27 (s, 1H), 7.94 (d, J=2.1 Hz,1H), 7.75 (s, 1H), 7.60 (s, 1H), 7.27 (s, 1H), 4.25-4.30 (m, 2H), 3.55(s, 3H), 3.34-3.27 (m, 2H), 2.12 (s, 3H), 1.79-1.84 (m, 2H), 1.18-1.33(m, 5H), 0.89-0.94 (m, 3H).

LCMS: 403 (M+H)⁺.

Example 41N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamideStep 1: 6-bromo-1-[(2,4-difluorophenyl)methyl]-4-nitrobenzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting 1-(bromomethyl)-2,4-difluorobenzene forbromomethylbenzene.

LCMS: 368; 370 (M+H⁺).

Step 2:N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 32, steps2-4, by substituting6-bromo-1-[(2,4-difluorophenyl)methyl]-4-nitrobenzimidazole for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole in step 2 andethanesulfonyl chloride for methanesulfonyl chloride in step 3. ¹H NMR(400 MHz, CDCl₃) δ 8.07 (m, 2H), 7.40-7.49 (m, 4H), 7.13 (s, 1H),6.90-6.92 (m, 2H), 5.44 (s, 2H), 3.64 (s, 3H), 3.19 (q, J=7.2 Hz, 2H),2.24 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LCMS: 473 (M+H)⁺.

Example 42N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indazol-4-yl]ethanesulfonamideStep 1: 1-benzyl-6-bromo-4-nitroindazole

To a mixture of 6-bromo-4-nitro-1H-indazole (500 mg, 2 mmol) in DMF (10mL) was added NaH (50 mg, 2 mmol) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 10 min and then BnBr (354 mg, 2 mmol)was added. The mixture was stirred at 25° C. for 12 hr. After this time,it was diluted with water and extracted with EtOAc (30 ml). The combinedorganic layers were concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:EA=25:1) to afford thetitle compound (150 mg, 22% yield) as solid. ¹H NMR (CDCl₃, 400 MHz) δ8.65 (d, J=0.8 Hz, 1H), 8.27 (m, 1H), 7.87 (s, 1H), 7.21-7.42 (m, 5H),5.66 (s, 2H). LCMS: 332.0 (M+H)⁺.

Step 2: 5-(1-benzyl-4 nitroindazol-6-yl)-1,3-dimethylpyridin-2-one

To a mixture of the title compound from step 1 (100 mg, 301 umol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(90 mg, 361 umol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) at 25° C. wasadded K₃PO₄ (127 mg, 602 umol) and Pd(dppf)Cl₂ (11 mg, 15 umol) in oneportion under N₂. The mixture was stirred at 90° C. for 12 hr. Aftercooling to RT, the reaction contents were concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EA=3:1˜1:1) followed by preparative HPLC to afford the titlecompound (50 mg, 44% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ8.67 (s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.47 (m, 2H), 7.21-7.35 (m,5H), 5.73 (s, 2H), 3.67 (s, 3H), 2.26 (s, 3H).

Step 3: 5-(4-amino-1-benzylindazol-6-yl)-1,3-dimethylpyridin-2-one

To a mixture of the title compound from step 2 (50 mg, 134 μmol) in EtOH(2 mL) and H₂O (1 mL) at RT was added NH₄Cl (36 mg, 667 μmol) and Fe (37mg, 667 μmol) in one portion under N₂. The mixture was stirred at 90° C.for 1 hr. It was then cooled to RT, filtered and concentrated underreduced pressure. The residue was diluted with water and extracted byEtOAc (20 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the titlecompound as a yellow solid that was used directly in the next stepwithout further purification. LCMS: 345.1 (M+H)⁺.

Step 4:N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indazol-4-yl]ethanesulfonamide

A mixture of the title compound from step 3 (100 mg, 290 μmol) andethanesulfonyl chloride (74 mg, 580 μmol) in pyridine (2 mL) was stirredat 25° C. for 4 hr. The reaction mixture was quenched with MeOH andpurified by preparative HPLC to afford the title compound (18.8 mg, 16%yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.16 (s, 1H), 7.51 (s, 1H), 7.43 (s,1H), 7.29-7.34 (m, 4H), 7.22-7.24 (m, 2H), 7.17 (m, 1H), 7.12 (s, 1H),5.63 (s, 2H), 3.67 (s, 3H), 3.22 (q, J=7.2 Hz, 2H), 2.25 (s, 3H), 1.41(t, J=7.2 Hz, 3H). LCMS: 437.0 (M+H)⁺.

Example 43 N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]indazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 42 bysubstituting 1-(bromomethyl)-4-fluorobenzene for bromomethylbenzene instep 1. ¹H NMR (CDCl₃, 400 MHz) δ 8.14 (s, 1H), 7.48 (s, 1H), 7.41 (d,J=2.4 Hz, 1H), 7.29 (s, 1H), 7.21 (m, 2H), 7.19 (s, 1H), 7.09 (m, 2H),5.58 (s, 2H), 3.65 (s, 3H), 3.22 (q, J=7.2 Hz, 2H), 2.25 (s, 3H), 1.41(t, J=7.2 Hz, 3H). LCMS: 455.0 (M+H)⁺.

Examples 44 and 45N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-[(1S)-(1-phenylethyl)]benzimidazol-4-yl]methanesulfonamideandN-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-[(1R)-(1-phenylethyl)]benzimidazol-4-yl]methanesulfonamideStep 1: 6-bromo-2-methyl-4-nitro-1-(1-phenylethyl)benzimidazole

The title compounds was prepared in a manner similar to Example 31, step3, by substituting 6-bromo-2-methyl-4-nitro-1H-benzimidazole for6-bromo-4-nitro-1H-benzimidazole and 1-bromoethylbenzene forbromomethylbenzene. ¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (s, 1H), 7.83 (s,1H), 7.46-7.25 (m, 5H), 6.12 (q, J=6.8 Hz, 1H), 3.30 (s, 3H), 2.60 (s,3H), 1.93 (d, J=6.8 Hz, 3H). LCMS: 360; 362 (M+H)⁺.

Step 2:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 32, steps2 through 4, by substituting6-bromo-2-methyl-4-nitro-1-(1-phenylethyl)benzimidazole for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole in step 2. ¹HNMR (400 MHz, DMSO-d₆): δ 9.50 (br, 1H), 7.77 (s, 1H), 7.52 (s, 1H),7.40-7.25 (m, 5H), 7.19 (s, 1H), 7.17 (s, 1H), 6.02 (q, J=6.8 Hz, 1H),3.50 (s, 3H), 3.30 (s, 3H), 3.20 (s, 3H), 2.07 (s, 3H), 1.97 (d, J=6.8Hz, 3H).

Step 3:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-[(1S)-(1-phenylethyl)]benzimidazol-4-yl]methanesulfonamideandN-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-[(1R)-(1-phenylethyl)]benzimidazol-4-yl]methanesulfonamide

The title compound from Step 2 was submitted to chiral phase HPLCseparation (Chiralcelpak IB, 250 mm*4.6 mm 5 um; MeOH: EtOH=50:50; Flow:1.0 ml/min) to afford its two enantioemers: Example 44 (Rt=5.454 min)and Example 45 (Rt=7.487 min). The absolute configuration has beenassigned randomly.

Example 46N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(2R)-1-methoxypropan-2-yl]-2-methylbenzimidazol-4-yl]methanesulfonamideStep 1: 5-bromo-3-fluoro-N-[(2R)-1-methoxypropan-2-yl]-2-nitroaniline

To a solution of (2R)-1-methoxypropan-2-amine (638 mg, 5.1 mmol) in DMF(15 mL) was added t-BuOK (1.08 g, 9.7 mmol). The mixture was stirred for30 min. 5-bromo-1,3-difluoro-2-nitrobenzene (1.1 g, 4.6 mmol) was addedand the reaction mixture was heated to 30° C. for 2 hr. It was thendiluted with water (40 mL) and DCM (40 mL). The mixture was acidified topH <6 by addition of AcOH. The organic layer was separated and theaqueous one was extracted with EtOAc (50 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE:EA=30:1 to 20:1) to give the title compound (600 mg,43%) as a brown solid. LCMS: 307; 309 (M+H)⁺.

Step 2:N-[5-bromo-3-[[(2R)-1-methoxypropan-2-yl]amino]-2-nitrophenyl]methanesulfonamide

To a solution of methanesulfonamide (280 mg, 2.95 mmol) in DMF (10 mL)was added t-BuOK (307 mg, 2.74 mmol). The mixture was stirred for 30min. 5-bromo-3-fluoro-N-[(2R)-1-methoxypropan-2-yl]-2-nitroaniline (600mg, 1.96 mmol) was added and the reaction was heated to 30° C. for 3 hr.The mixture was diluted with water (40 mL) followed by dropwise additionof AcOH to pH <6 and extraction with EtOAc (50 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE:EA=20:1) to give the title compound (400 mg, 54%) asa brown solid. ¹H NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 7.07 (d, J=1.5Hz, 1H), 6.86 (d, J=1.5 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 4.00-3.88 (m,1H), 3.40 (d, J=4.8 Hz, 2H), 3.29 (s, 3H), 3.12 (s, 3H), 1.14 (d, J=6.6Hz, 3H). LCMS: 382; 384 (M+H)⁺.

Step 3:N-[2-amino-5-bromo-3-[[(2R)-1-methoxypropan-2-yl]amino]phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 32, step2, by substituting the title compound from step 2 for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole. ¹H NMR (300MHz, CDCl3): δ 6.83 (s, 1H), 6.81 (s, 1H), 3.65-3.57 (m, 1H), 3.44 (d,J=3.3 Hz, 2H), 3.39 (s, 3H), 3.05 (s, 3H), 1.24 (d, J=4.8 Hz, 3H).

LCMS: 352; 354 (M+H)⁺.

Step 4:N-[6-bromo-1-[(2R)-1-methoxypropan-2-yl]-2-methylbenzimidazol-4-yl]methanesulfonamide

To a suspension of the title compound from step 3 (80 mg, 0.23 mmol) inEtOH (5 mL) was added 5 M HCl (3 mL). The reaction mixture was heated toreflux followed by addition of pentane-2,4-dione (0.17 mL, 0.46 mmol) inone portion. After 1 hr, the mixture was cooled to RT and neutralizedwith concentrated ammonium hydroxide. The mixture was extracted with DCM(50 mL×2). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give the title compound (74mg, 87%) as a yellow solid. LCMS: 376; 378 (M+H)⁺.

Step 5:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(2R)-1-methoxypropan-2-yl]-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 31, step6, by substituting the title compound from step 4 forN-(1-benzyl-6-bromobenzimidazol-4-yl)methanesulfonamide. ¹H NMR (300MHz, DMSO-d₆): δ 9.47 (br, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.53 (s,1H), 7.19 (s, 1H), 4.86-4.72 (m, 1H), 3.99-3.82 (m, 1H), 3.72-3.64 (m,1H), 3.55 (s, 3H), 3.20 (s, 6H), 2.57 (s, 3H), 2.11 (s, 3H), 1.58 (d,J=7.2 Hz). LCMS: 419 (M+H)⁺.

Example 47N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamideStep 1: N-(3-chloro-2-hydroxy-5-nitrophenyl)cyclopropanecarboxamide

A solution of 2-amino-6-chloro-4-nitrophenol (1.88 g, 10 mmol) in amixture of pyridine (80 mL) and DCM (20 mL) stirred at 0° C. under anatmosphere of nitrogen was treated with cyclopropanecarbonyl chloride(904 uL, 10 mmol) by dropwise over 10 min. The mixture was allowed togradually warm to rt. After stirring for 12 hr, the mixture was treatedwith water (20 mL) and then concentrated to near dryness in vacuo. Theresulting mixture was treated with additional water (80 mL) and wasstirred vigorously for 10 min. The resulting suspension was filtered;the filter cake was washed with water (50 ml) and hexanes (50 ml) anddried in vacuo to afford the title compound (2.38 g, 99%) as a tansolid.

Step 2: 7-chloro-2-cyclopropyl-5-nitro-1,3-benzoxazole

A mixture of N-(3-chloro-2-hydroxy-5-nitrophenyl)cyclopropanecarboxamide(2.38 g, 9.3 mmol) and pyridinium p-toluenesulfonate (466 mg, 1.9 mmol)suspended in xylenes (62 mL) was heated to 150° C. in a sealed tube for12 hr. The crude reaction mixture was filtered through a short plug ofcelite; the celite plug was washed with MeOH (˜10 mL). The resultingfiltrate was concentrated in vacuo. The resulting residue was dilutedwith EtOAc (50 ml) and washed with saturated bicarbonate solution (aq),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography using a gradient of MeOH (0 to 10%) in DCM to afford thetitle compound (711 mg, 98%) as a brown solid. LCMS (M+H)⁺=239.

Step 3:5-(2-cyclopropyl-5-nitro-1,3-benzoxazol-7-yl)-1,3-dimethylpyridin-2-one

A mixture of 7-chloro-2-cyclopropyl-5-nitro-1,3-benzoxazole (91 mg, 0.38mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(108 mg, 0.44 mmol), K₃PO₄ (247 mg, 1.1 mmol), Pd₂(dba)₃ (17 mg, 5%) andS-Phos (16 mg, 10%) in dioxane (2.4 mL) and H₂O (120 uL) was bubbledwith nitrogen for 5 min. The sealed vial was stirred at 80° C. for 180min. After the reaction mixture was filtered through a short plug ofcelite, the celite plug was washed with EtOAc (35 mL). The filtrate waswashed with water and brine; the organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to afford a tan residue. Theresulting residue was purified by silica gel column chromatography usinga gradient of EtOAc (0 to 100%) in DCM to afford the title compound (71mg, 57%) as a tan solid. LCMS (M+H)⁺=326.

Step 4:5-(5-amino-2-cyclopropyl-1,3-benzoxazol-7-yl)-1,3-dimethylpyridin-2-one

A solution of5-(2-cyclopropyl-5-nitro-1,3-benzoxazol-7-yl)-1,3-dimethylpyridin-2-one(71 mg, 0.22 mmol) in a mixture of THF (770 uL), MeOH (770 uL), andwater (260 uL) was treated with Iron (62 mg, 1.1 mmol) and NH₄Cl (30 mg,0.55 mmol). The mixture was heated to 90° C. for 3 hr. After cooling tort, the mixture was filtered through a short bed of celite; the filtratewas partitioned between water and EtOAc (40 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to give thetitle compound (55 mg, 85%) as a yellow solid.

LCMS (M+H)⁺=296.

Step 5:N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide

Ethylsulfonyl chloride (18 uL, 0.19 mmol) was added to a solution of5-(5-amino-2-cyclopropyl-1,3-benzoxazol-7-yl)-1,3-dimethylpyridin-2-one(55 mg, 0.19 mmol) and pyridine (61 uL, 0.57 mmol) in DCM (1 mL) stirredat 0° C. under nitrogen. The mixture was allowed to warm to rt. Afterstirring for 12 hr, the mixture was treated with 1N HCl (2 mL) andextracted with DCM (3×15 mL); the combined organic extracts were washedwith saturated bicarbonate solution (aq), dried over sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedby prep-HPLC to afford the title compound (36 mg, 56%) as a tan solid.¹H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.24 (m, 7H) 2.07-2.15 (m, 3H)2.26-2.36 (m, 1H) 3.03-3.14 (m, 2H) 3.53-3.59 (m, 3H) 7.23-7.28 (m, 1H)7.32-7.36 (m, 1H) 7.68-7.76 (m, 1H) 8.09 (m, 1H) 9.67-9.85 (bs, 1H).LCMS (M+H)⁺=388.

Example 48N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamideStep 1:4-(2-cyclopropyl-5-nitro-1,3-benzoxazol-7-yl)-2-methylisoquinolin-1-one

A mixture of 7-chloro-2-cyclopropyl-5-nitro-1,3-benzoxazole (70 mg, 0.31mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(100 mg, 0.35 mmol), K₃PO₄ (202 mg, 0.93 mmol), Pd₂(dba)₃ (14 mg, 5%)and S-Phos (13 mg, 10%) in dioxane (2.0 mL) and H₂O (100 uL) was bubbledwith nitrogen for 5 min. The sealed vial was stirred at 85° C. for 12hr. After the reaction mixture was filtered through a short plug ofcelite, the celite plug was washed with EtOAc (25 mL). The filtrate waswashed with water and brine; the organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to afford a tan residue. Theresulting residue was purified by silica gel column chromatography usinga gradient of EtOAc (0 to 100%) in DCM to afford the title compound (73mg, 65%) as a tan solid. LCMS (M+H)⁺=362.

Step 2:4-(5-amino-2-cyclopropyl-1,3-benzoxazol-7-yl)-2-methylisoquinolin-1-one

A solution of4-(2-cyclopropyl-5-nitro-1,3-benzoxazol-7-yl)-2-methylisoquinolin-1-one(73 mg, 0.20 mmol) in a mixture of THF (700 uL), MeOH (700 uL), andwater (266 uL) was treated with Iron (57 mg, 1.0 mmol) and NH₄Cl (22 mg,0.4 mmol). The mixture was heated to 90° C. for 4 hr. After cooling tort, the mixture was filtered through a short bed of celite; the filtratewas partitioned between water and EtOAc (40 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to give thetitle compound (58 mg, 85%) as a yellow solid.

LCMS (M+H)⁺=332.

Step 3:N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide

Ethylsulfonyl chloride (170 uL, 1.8 mmol) was added to a solution of4-(5-amino-2-cyclopropyl-1,3-benzoxazol-7-yl)-2-methylisoquinolin-1-one(440 mg, 1.8 mmol) and pyridine (725 uL) in DCM (4.5 mL) stirred at 0°C. under nitrogen. The mixture was allowed to warm to rt and stir for 12h: the mixture was treated with 1N HCl (5 mL) and extracted with DCM(3×50 mL); the combined organic extracts were washed with saturatedbicarbonate solution (aq), dried over sodium sulfate, filtered andconcentrated in vacuo. The resulting residue was purified by prep-HPLCto afford the title compound (34 mg, 71%) as a tan solid. 1H NMR (400MHz, DMSO-d6) δ ppm 0.99-1.07 (m, 2H) 1.07-1.17 (m, 2H) 1.18-1.27 (m,3H) 2.15-2.27 (m, 1H) 3.08-3.20 (m, 2H) 3.56-3.65 (m, 3H) 7.15-7.25 (m,1H) 7.26-7.36 (m, 1H) 7.47-7.53 (m, 1H) 7.53-7.62 (m, 1H) 7.65-7.77 (m,2H) 8.31-8.41 (m, 1H) 9.83-9.94 (bs, 1H). LCMS (M+H)⁺=424.

Example 494-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-2-methylisoquinolin-1-oneStep 1: 6-bromo-7-hydroxy-4H-1,4-benzoxazin-3-one

A solution of 7-hydroxy-4H-1,4-benzoxazin-3-one (165 mg, 1 mmol) inacetic acid (5.6 mL) stirred in the dark at 10° C. was treated with asolution of Br₂ (168 mg, 1.05 mmol) in acetic acid (1 mL) dropwise over15 min. The reaction mixture was allowed to warm gradually to rt. After90 min, the mixture was treated with 10% sodium thiosulfate (aq) (3 mL).After the mixture was concentrated in vacuo, the resulting residue wastreated with water, sonicated for 3 min and filtered. The filter cakewas washed with Et₂O and dried in vacuo to afford the title compound(243 mg, 99%) as a white solid. LCMS (M+H)⁺=246.

Step 2: 6-bromo-7-(cyclopropylmethoxy)-4H-1,4-benzoxazin-3-one

A solution of 6-bromo-7-hydroxy-4H-1,4-benzoxazin-3-one (243 mg, 0.99mmol) in DMF (4 mL) stirred at 0° C. was treated K₂CO₃ (152 mg, 1.09mmol). After 15 min the reaction mixture was treated withbromomethylcyclopropane (165 uL, 1.09 mmol). The reaction mixture wasallowed to warm gradually to rt. After stirring for 12 hr, the mixturewas treated with water and extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford the title compound (232 mg, 78%) as atan solid. LCMS (M+H)⁺=299.

Step 3: 6-bromo-7-(cyclopropylmethoxy)-3,4-dihydro-2H-1,4-benzoxazine

A solution of borane in THF (1.0 M, 1.2 mL, 1.2 mmol) was added to anice-cold solution of6-bromo-7-(cyclopropylmethoxy)-4H-1,4-benzoxazin-3-one (230 mg, 0.77mmol) in THF (5 mL). The ice bath was removed and the reaction wasallowed to warm to rt. After 30 min, the flask was fitted with a refluxcondenser and was heated to 70° C. under nitrogen. After 2 hr, themixture was cooled to 0° C. and quenched with 1 N NaOH (2 mL). After themixture was stirred for 15 min, it was diluted with water (5 mL) andevaporated to remove THF. The aqueous residue was extracted with EtOAcand washed with water (5 mL) and 0.5 N NaOH (5 mL). The organic layerwas washed with brine, dried over MgSO₄, filtered and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography using a gradient of EtOAc (10 to 90%) in DCM to affordthe title compound (219 mg, 78%) as a white solid. LCMS (M+H)⁺=285.

Step 4:6-bromo-7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazine

Ethylsulfonyl chloride (94 uL, 0.96 mmol) was added to a solution of6-bromo-7-(cyclopropylmethoxy)-3,4-dihydro-2H-1,4-benzoxazine (219 mg,0.77 mmol) and pyridine (310 μL) in DCM (4 mL) stirred at 0° C. undernitrogen. After the mixture was allowed to warm to RT and stirred for 12hr, it was treated with 1N HCl (10 mL) and extracted with DCM (3×10 mL);the combined organic extracts were washed with saturated bicarbonatesolution (aq), dried over sodium sulfate, filtered and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography using a gradient of EtOAc (10 to 50%) in DCM to affordthe title compound (277 mg, 96%) as a white solid. LCMS (M+H)⁺=377.

Step 5:4-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-2-methylisoquinolin-1-one

A mixture of6-bromo-7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazine(100 mg, 0.27 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(76 mg, 0.27 mmol), K₃PO₄ (145 mg, 0.66 mmol), Pd(dppf)Cl₂ (19 mg, 10%)in dioxane/H₂O (1.6 mL/177 μL) was bubbled with nitrogen for 5 min. Thesealed vial was stirred at 77° C. for 4 hr. The reaction mixture wasfiltered through a short plug of celite; the celite plug was washed withEtOAc (15 mL). The filtrate was washed with water and brine; the organiclayer was dried over sodium sulfate, filtered and concentrated in vacuoto afford a tan residue. The resulting residue was purified by prep-HPLCto afford the title compound (58 mg, 48%) as a tan solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.02-0.11 (m, 4H) 0.18-0.39 (m, 2H) 0.80-0.95 (m,1H) 1.14-1.29 (m, 3H) 3.51-3.61 (m, 3H) 3.64-3.96 (m, 4H) 4.25-4.37 (m,2H) 6.60-6.75 (m, 1H) 7.14-7.25 (m, 1H) 7.34-7.43 (m, 2H) 7.43-7.56 (m,1H) 7.56-7.70 (m, 1H) 8.21-8.32 (m, 1H). LCMS (M+H)⁺=455.

Example 505-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-1,3-dimethylpyridin-2-one

The title compound (44 mg, 43%) was prepared as a tan solid in a similarmanner to step 5 of Example 49 except that1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewas substituted for2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.25-0.35 (m, 2H) 0.47-0.57 (m, 2H)1.09-1.27 (m, 4H) 2.00-2.07 (m, 3H) 3.27-3.39 (m, 2H) 3.44-3.52 (m, 3H)3.72-3.87 (m, 4H) 4.21-4.32 (m, 2H) 6.55-6.63 (m, 1H) 7.32-7.39 (m, 1H)7.43-7.49 (m, 1H) 7.59-7.67 (m, 1H). LCMS (M+H)⁺=419.

Example 51N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]propane-2-sulfonamide

The title compound (53 mg) was prepared as a tan solid in a similarmanner to step 5 of Example 47 except that propane-2-sulfonyl chloridewas substituted for ethylsulfonyl chloride.

LCMS (M+H)⁺=402.

Example 52N-[2-cyclopentyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide

The title compound (16 mg) was prepared as a tan solid in a similarmanner to Example 47 except that cyclopentanecarbonyl chloride wassubstituted for cyclopropane-carbonyl chloride in step 1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17-1.24 (m, 3H) 1.61-1.82 (m, 4H) 1.90-2.02 (m,2H) 2.04-2.16 (m, 5H) 3.05-3.13 (m, 2H) 3.40-3.50 (m, 1H) 3.55-3.59 (m,3H) 7.27-7.32 (m, 1H) 7.39-7.43 (m, 1H) 7.72-7.76 (m, 1H) 8.07-8.12 (m,1H) 9.61-9.93 (m, 1H). LCMS (M+H)⁺=416.

Example 53N-[2-cyclopentyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide

The title compound (42 mg) was prepared as a tan solid in a similarmanner to Example 47 except that cyclopentanecarbonyl chloride wassubstituted for cyclopropane-carbonyl chloride in step 1 and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewas substituted for1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.29 (m, 3H) 1.54-1.74(m, 4H) 1.79-1.93 (m, 2H) 1.94-2.06 (m, 2H) 3.08-3.19 (m, 2H) 3.59 (s,3H) 7.21-7.27 (m, 1H) 7.28-7.34 (m, 1H) 7.55-7.62 (m, 2H) 7.64-7.71 (m,1H) 7.73 (s, 1H) 8.31-8.39 (m, 1H) 9.86-9.94 (bs, 1H). LCMS (M+H)⁺=452.

Example 54N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-3-methylbenzimidazol-5-yl]ethanesulfonamideStep 1: 4-bromo-2-cyclopropyl-1-methyl-6-nitrobenzimidazole

A mixture of 4-bromo-2-cyclopropyl-6-nitro-1H-benzimidazole (732 mg, 2.6mmol) and K₂CO₃ (1.07 g, 7.8 mmol) stirred at rt in DMF (8.6 mL) undernitrogen was treated with MeI (517 mg, 3.6 mmol). The resultingsuspension was heated to 60° C. for 30 min before being stirred at RTfor 13 hr. The reaction mixture was treated water and was extracted withEtOAc. The combined organic layers were washed with water, brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel column chromatography using a gradient of EtOAc(10 to 100%) in DCM to afford the title compound (320 mg, 85%) as a redsolid.

LCMS (M+H)⁺297.

Step 2: 7-bromo-2-cyclopropyl-3-methylbenzimidazol-5-amine

4-bromo-2-cyclopropyl-1-methyl-6-nitrobenzimidazole (317 mg, 1.07 mmol)was dissolved in a mixture of THF (3 mL), MeOH (3 mL), and water (1.1mL) and was treated with Iron (181 mg, 5.4 mmol) and NH₄Cl (144 mg, 2.7mmol). The mixture was heated to 90° C. for 4 hr. After cooling to rt,the mixture was filtered through a short bed of celite; the filtrate waspartitioned between water and EtOAc (20 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to give thetitle compound (260 mg, 91%) as a tan solid.

LCMS (M+H)⁺266.

Step 3:N-(7-bromo-2-cyclopropyl-3-methylbenzimidazol-5-yl)ethanesulfonamide

Ethylsulfonyl chloride (111 μL, 1.2 mmol) was added to a solution of7-bromo-2-cyclopropyl-3-methylbenzimidazol-5-amine (260 mg, 0.98 mmol)and pyridine (500 uL) in DCM (5 mL) stirred at 0° C. under nitrogen.After the mixture was allowed to warm to rt and stir for 12 hr, it wastreated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); thecombined organic extracts were washed with saturated bicarbonatesolution (aq), dried over Na₂SO₄, filtered and concentrated in vacuo.The resulting residue was purified by silica gel column chromatographyusing a gradient of EtOAc (0 to 70%) in DCM to afford the title compound(279 mg, 80%) as an off-white solid. LCMS (M+H)⁺=359.

Step 4:N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-3-methylbenzimidazol-5-yl]ethanesulfonamide

A mixture ofN-(7-bromo-2-cyclopropyl-3-methylbenzimidazol-5-yl)ethanesulfonamide (60mg, 0.17 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(41 mg, 0.17 mmol), K₃PO₄ (91 mg, 0.42 mmol), Pd(dppf)Cl₂ (12 mg, 10%)in dioxane/H₂O (1 mL/120 μL) was bubbled with nitrogen for 5 min. Thesealed vial was stirred at 70° C. for 12 hr. The reaction mixture wasfiltered through a short plug of celite; the celite plug was washed withEtOAc (15 mL). The filtrate was washed with water and brine; the organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toafford a tan residue. The resulting residue was purified by prep-HPLC toafford the title compound (30 mg, 44%) as a white solid. LCMS(M+H)⁺=401.

Example 55N-[2-cyclopropyl-3-methyl-7-(2-methyl-1-oxoisoquinolin-4-yl)benzimidazol-5-yl]ethanesulfonamide

The title compound (42 mg, 59%) was prepared as a white solid in asimilar manner to step 4 of Example 54 except that2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewas substituted for1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.88 (m, 2H) 0.92-1.03 (m, 2H)1.18-1.27 (m, 3H) 2.12-2.26 (m, 1H) 3.05-3.16 (m, 3H) 3.58 (s, 3H) 3.84(s, 3H) 6.99-7.06 (m, 1H) 7.24-7.30 (m, 1H) 7.33-7.37 (m, 1H) 7.52 (s,3H) 8.29-8.35 (m, 1H) 9.64-9.75 (m, 1H). LCMS (M+H)⁺=437.

Example 565-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazol-7-yl]-1,3-dimethylpyridin-2-oneStep 1: methyl 3-bromo-5-(cyclopropanecarbonylamino)-4-hydroxybenzoate

The title compound (690 mg, 92%) was prepared as a light yellow solid ina similar manner to step 1 of Example 47 except that methyl3-amino-5-bromo-4-hydroxybenzoate was substituted for2-amino-6-chloro-4-nitrophenol. LCMS (M+H)⁺=315.

Step 2: methyl 7-bromo-2-cyclopropyl-1,3-benzoxazole-5-carboxylate

The title compound (410 mg, 63%) was prepared as a white solid in asimilar manner to step 2 of Example 47 except that methyl3-bromo-5-(cyclopropanecarbonylamino)-4-hydroxybenzoate was substitutedfor N-(3-chloro-2-hydroxy-5-nitrophenyl)cyclopropanecarboxamide. LCMS(M+H)⁺=297.

Step 3: (7-bromo-2-cyclopropyl-1,3-benzoxazol-5-yl)methanol

A solution of DIBAL in hexanes (1.0 M, 3.4 mL, 3.4 mmol) was addeddropwise over 7 min to an ice-cold solution of methyl7-bromo-2-cyclopropyl-1,3-benzoxazole-5-carboxylate (404 mg, 1.36 mmol)in THF (6.8 mL). After 15 min, the ice bath was removed and the reactionwas allowed to warm to rt. After 12 hr, the reaction was cooled to 0° C.and was treated with a saturated aqueous solution of potassium sodiumtartrate (8 mL). After the mixture was stirred vigorously for 30 min, itwas diluted with water (5 mL) and evaporated to remove THF. The aqueousresidue was extracted with EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The resulting residue was purified by silica gel column chromatographyusing a gradient of EtOAc (0 to 100%) in hexanes to afford the titlecompound (250 mg, 68%) as a tan solid. LCMS (M+H)⁺=269.

Step 4: 7-bromo-5-(bromomethyl)-2-cyclopropyl-1,3-benzoxazole

A 0.15 M solution of (7-bromo-2-cyclopropyl-1,3-benzoxazol-5-yl)methanol(248 mg, 0.93 mmol) in DCM stirred at 0° C. under an atmosphere ofnitrogen was treated with PBr₃ (87 μL, 0.93 mmol). The ice bath wasremoved and the reaction mixture was allowed to stir at rt for 3 hr. Thereaction mixture was cooled to 0° C., treated with water and extractedwith EtOAc. The combined organic layers were washed with water, brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography using a gradient of EtOAc (10 to100%) in hexanes to afford the title compound (142 mg, 46%) as a tansolid. LCMS (M+H)⁺=332.

Step 5: 7-bromo-2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazole

A 0.4 M solution of7-bromo-5-(bromomethyl)-2-cyclopropyl-1,3-benzoxazole (32 mg, 0.1 mmol)in DMF (20 mL) stirred at rt under an atmosphere of nitrogen was treatedwith sodium methanesulfinate (85%, 40 mg, 0.4 mmol). After the mixturewas heated to 50° C. for 3 hr, it was stirred at RT for 48 hr. Themixture was treated with water (3 mL), sonicated for 2 min and filtered;the filter cake was washed with water (5 ml) and hexanes (5 ml) anddried in vacuo to afford the title compound (30 mg, 99%) as a whitesolid. LCMS (M+H)⁺=331.

Step 6:5-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazol-7-yl]-1,3-dimethylpyridin-2-one

A mixture of7-bromo-2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazole (30 mg,0.1 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(22 mg, 0.1 mmol), K₃PO₄ (50 mg, 0.25 mmol), Pd(dppf)Cl₂ (7 mg, 10%) indioxane/H₂O (600 L/50 uL) was bubbled with nitrogen for 7 min. Thesealed vial was stirred at 70° C. for 12 hr. The reaction mixture wasfiltered through a short plug of celite; the celite plug was washed withEtOAc (15 mL). The filtrate was washed with water and brine; the organiclayer was dried over sodium sulfate, filtered and concentrated in vacuoto afford a tan residue. The resulting residue was purified by silicagel column chromatography using a gradient of MeOH (0 to 5%) in DCM toafford the title compound (26 mg, 72%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.78-0.94 (m, 4H) 2.12 (s, 3H) 2.29-2.41 (m,1H) 2.91 (s, 3H) 3.57 (s, 3H) 4.52-4.63 (m, 2H) 7.51-7.58 (m, 2H)7.80-7.85 (m, 1H) 8.13-8.18 (m, 1H). LCMS (M+H)⁺=373.

Example 57N-[2-cyclopentyl-7-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide

The title compound (42 mg) was prepared as a pink solid in a similarmanner to Example 47 except that cyclopentanecarbonyl chloride wassubstituted for cyclopropane-carbonyl chloride in step 1 and3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewas substituted for1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.28 (m, 3H) 1.60-1.83(m, 4H) 1.91-2.03 (m, 2H) 2.05-2.18 (m, 2H) 3.04-3.15 (m, 2H) 3.40-3.51(m, 1H) 3.57 (s, 3H) 3.80 (s, 3H) 7.18-7.27 (m, 1H) 7.30-7.37 (m, 1H)7.41-7.46 (m, 1H) 7.77-7.84 (m, 1H) 9.71-9.85 (bs, 1H). LCMS (M+H)⁺=432.

Example 585-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-1,3-dimethylpyridin-2-one

A mixture of the title compound of Example 29, step 5 (40 mg, 0.11mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(33 mg, 0.13 mmol), K₂CO₃ (46 mg, 0.33 mmol) and Pd(dppf)Cl₂ (8 mg, 0.01mmol) in dioxane (6 mL) and H₂O (2 mL) was heated at 85° C. for 1 hr,cooled, diluted with H₂O (20 mL), and extracted with DCM (35 mL×2). Thecombined organic layers were dried over Na₂SO₄, filtered, concentrated,and the residue was purified using prep-TLC (PE/EtOAc 1:1) to give thetitle compound (21 mg, 46%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 7.76 (s, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 4.12 (s, 3H),4.02 (d, J=7.2 Hz, 2H), 3.51 (s, 3H), 3.33 (s, 3H), 2.06 (s, 3H),1.29-1.24 (m, 1H), 0.61-0.56 (m, 2H), 0.39-0.35 (m, 2H). LCMS: 402(M+H⁺).

Example 595-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-3-methoxy-1-methylpyridin-2-one

A mixture of the title compound of Example 29, step 5 (48 mg, 0.13mmol),3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(42 mg, 0.16 mmol), K₂CO₃ (56 mg, 0.41 mmol) and Pd(dppf)Cl₂ (10 mg,0.01 mmol) in dioxane (6 mL) and H₂O (2 mL) was heated at 85° C. for 2hr, cooled to RT, diluted with H₂O (30 mL), and extracted with DCM (30mL×2). The combined organic layers were dried over Na₂SO₄, filtered,concentrated, and the residue was purified using prep-TLC (EtOAc) togive the title compound (26 mg, 46%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.99 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 6.80 (s, 1H), 4.17(s, 3H), 3.98 (d, J=6.4 Hz, 2H), 3.91 (s, 3H), 3.70 (s, 3H), 3.32 (s,3H), 1.37-1.31 (m, 1H), 0.73-0.71 (m, 2H), 0.43-0.42 (m, 2H). LCMS: 418(M+H⁺).

Example 60N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamideStep 1:4,6-dichloro-1-[(4-fluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridine

A mixture of 4,6-dichloro-2-methyl-1H-imidazo[4,5-c]pyridine (400 mg,1.99 mmol), K₂CO₃ (414 mg, 3.0 mmol) and 4-fluorobenzyl bromide (454 mg,2.39 mmol) in DMF (5 mL) was stirred at RT overnight. The mixture waspartitioned between water (50 mL) and DCM (30 mL) and extracted with DCM(50 mL*2). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, concentrated, and purified using silica gelchromatography (PE:EA=5:1) to give the title compound (400 mg, 65%) as abrown solid. ¹H NMR (300 MHz, DMSO-d₆): δ7.90 (s, 1H), 7.29-7.12 (m,4H), 5.53 (s, 2H), 2.55 (s, 3H). LCMS: 310, 312 (M+H⁺).

Step 2:N-[6-chloro-1-[(4-fluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamide

The title compound of step 1 (1.0 g, 3.2 mmol), methanesulfonamide (461mg, 4.9 mmol) (AcO)₂Pd (72 mg, 0.32 mmol), Xantphos (203 mg, 0.35 mmol)and Cs₂CO₃ (1.36 g, 4.16 mmol) in DMF (8 mL) were microwaved at 120° C.under N₂ for 10 hr. The mixture was partitioned between water (50 mL)and DCM (30 mL) and extracted with DCM (50 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered,concentrated, and purified using silica gel chromatography (PE:EA=5:1)to give the title compound (318 mg, 27%) as a white solid. ¹H NMR (300MHz, DMSO-d₆): δ 11.10 (br, 1H), 7.52 (s, 1H), 7.26-7.17 (m, 4H), 5.49(s, 2H), 3.46 (s, 3H), 2.52 (s, 3H). LCMS: 369 (M+H⁺).

Step 3:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamide

The title compound of step 2 (200 mg, 0.54 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(161 mg, 0.65 mmol), KOAc (159 mg, 1.62 mmol) anddichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladiumII (35 mg,0.054 mmol) in DMF/H₂O (5 mL/1.0 mL) under N₂ were heated at 100° C.overnight, cooled, filtered, and the filtrate diluted with H₂O andextracted with EtOAc (50 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated, and purified using prep-TLC (DCM:MeOH=15:1)followed by prep-HPLC to give the title compound (57 mg, 23%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 10.70 (br, 1H), 8.23 (s, 1H), 8.06(s, 1H), 7.84 (s, 1H), 7.26-7.12 (m, 4H), 5.51 (s, 2H), 3.54 (s, 3H),3.51 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H). LCMS: 456 (M+H⁺).

Example 61N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylimidazo[4,5-c]pyridine-4-yl]methanesulfonamide

A three step synthesis was carried out in a similar manner as Example 60except that benzyl bromide was substituted for 4-fluorobenzyl bromide instep 1. After purification, the title compound (52 mgs) was obtained asa white solid in 2% overall yield for the three steps. ¹H NMR (400 MHz,DMSO-d₆): δ 10.70 (br, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H),7.36-7.12 (m, 5H), 5.53 (s, 2H), 3.53 (s, 3H), 3.52 (s, 3H), 2.48 (s,3H), 2.10 (s, 3H). LCMS: 438 (M+H⁺).

Example 62N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamide

A three step synthesis was carried out in a similar manner as Example 60except that 2,4-difluorobenzyl bromide was substituted for4-fluorobenzyl bromide in step 1. After purification, the title compound(37 mgs) was obtained as a white solid in 1% overall yield for the threesteps. ¹H NMR (300 MHz, DMSO-d₆): δ 10.66 (br, 1H), 8.20 (s, 1H), 8.02(s, 1H), 7.78 (s, 1H), 7.39-6.92 (m, 3H), 5.56 (s, 2H), 3.54 (s, 3H),3.51 (s, 3H), 2.50 (s, 3H), 2.10 (s, 3H). LCMS: 474 (M+H⁺).

Example 635-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3-benzoxazol-7-yl]-3-methoxy-1-methylpyridin-2-one

The title compound (21 mg) was prepared as a white solid in a similarmanner to Example 56 except that3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewas substituted for1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.28 (m, 4H) 2.30-2.42(m, 1H) 2.86-2.99 (s, 3H) 3.53-3.64 (s, 3H) 3.82 (s, 3H) 4.46-4.67 (s,2H) 7.24-7.32 (m, 1H) 7.52-7.61 (m, 2H) 7.84-7.90 (m, 1H). LCMS(M+H)⁺=389.

Example 64N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-4-yl]methanesulfonamideStep 1: 6-bromo-3-fluoro-4-nitro-1H-indazole

To a mixture of 6-bromo-4-nitro-1H-indazole (3 g, 6.2 mmol) in ACN (30mL) and CH₃COOH (6 mL) was added Selectfluor (8.76 g, 12.4 mmol) in oneportion at 25° C. under N₂. The mixture was stirred at 100° C. for 2days. It was concentrated under reduced pressure, diluted with DCM (50mL) and filtered. The filtrate was concentrated under reduced pressureand purified by silica gel column chromatography (PE:EA=20:1) andpreparative HPLC to the title compound (1.2 g, 37%). ¹H NMR (CDCl₃, 400MHz) δ 8.22 (s, 1H), 7.94 (s, 1H).

Step 2: 6-bromo-3-fluoro-1-[(4-fluorophenyl)methyl]-4-nitroindazole

To the title compound from step 1 (200 mg, 770 μmol) in THF (3 mL) wasadded NaH (40 mg, 1000 μmol) at 0° C. under a N₂ atmosphere. The mixturewas stirred at that temperature for 10 min before addition of1-(bromomethyl)-4-fluoro-benzene (190 mg, 1000 μmol). The reactionmixture was stirred at 25° C. for 12 hr. It was then concentrated underreduced pressure and purified by silica gel column chromatography(PE:EA=20:1) to give the title compound (220 mg, 78%). ¹H NMR (CDCl₃,400 MHz) δ 8.16 (d, J=1.2 Hz, 1H), 7.79 (s, 1H), 7.24 (m, 2H), 7.06 (m,2H), 5.43 (s, 2H).

Step 3:5-[3-fluoro-1-[(4-fluorophenyl)methyl]-4-nitroindazol-6-yl]-1,3-dimethylpyridin-2-one

To a mixture of the title compound from step 2 (110 mg, 300 μmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(97 mg, 390 umol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was added K₃PO₄(127 mg, 600 μmol) and Pd(dppf)Cl₂ (11 mg, 15 μmol) in one portion underN₂. The mixture was stirred at 90° C. for 12 hr. After cooling to RT, itwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (PE:EA=20:1) to afford the titlecompound (110 mg, 90% yield) as a yellow solid.

LCMS: 411 (M+H)⁺.

Step 4:5-[4-amino-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-6-yl]-1,3-dimethylpyridin-2-one

To the title compound from step 3 (110 mg, 268 umol) in EtOH (6 mL) andH₂O (3 mL) was added NH₄Cl (72 mg, 1.34 mmol) and Fe (75 mg, 1.34 mmol)in one portion under N₂. The reaction was stirred at 100° C. for 1 hr.The mixture was filtered, basified and extracted with DCM (30 mL). Theorganic layer was concentrated under reduced pressure to afford thetitle compound that was used directly in next step without furtherpurification. LCMS: 381.1 (M+H⁺).

Step 5:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 17, step4, by substituting5-[4-amino-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-6-yl]-1,3-dimethylpyridin-2-onefor 1-benzyl-6-bromoindol-4-amine. ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (s,1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.23-7.24 (m, 2H), 7.01-7.06 (m, 3H),6.89 (s, 1H), 5.39 (s, 2H), 3.65 (s, 3H), 3.15 (s, 3H), 2.25 (s, 3H).LCMS: 459.0 (M+H⁺).

Example 65N-[3-fluoro-1-[(4-fluorophenyl)methyl]-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)indazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 64 bysubstituting3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 3. ¹H NMR (CDCl₃, 400 MHz) δ 7.34 (s, 1H), 7.25-7.27 (m, 2H),7.17 (d, J=2.4 Hz, 1H), 7.06-7.08 (m, 2H), 7.00 (s, 1H), 6.81 (m, 1H),6.80 (s, 1H), 5.42 (s, 2H), 3.92 (s, 3H), 3.69 (s, 3H), 3.16 (s, 3H).LCMS: 475.1 (M+H⁺).

Example 66N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 64 bysubstituting bromomethylcyclopropane for1-(bromomethyl)-4-fluoro-benzene in step 2. ¹H NMR (CDCl₃, 400 MHz) δ7.52 (s, 1H), 7.47 (s, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 6.87 (s, 1H),4.12 (d, J=7.2 Hz, 2H), 3.67 (s, 3H), 3.14 (s, 3H), 2.27 (s, 3H), 1.31(m, 1H), 0.63 (m, 2H), 0.43 (m, 2H). LCMS: 405.0 (M+H)⁺.

Example 675-(3-benzyl-2-methyl-7-methylsulfonylbenzimidazol-5-yl)-1,3-dimethylpyridin-2-oneStep 1: N-benzyl-5-bromo-3-fluoro-2-nitroaniline

A mixture of 5-bromo-1,3-difluoro-2-nitrobenzene (3.00 g, 12.6 mmol),K₂CO₃ (8.7 g, 63 mmol) and benzyl amine (1.35 g, 12.6 mmol) in THF (150mL) was stirred at RT for 3 hr. The reaction mixture was diluted withwater (300 mL) and DCM (100 mL). The aqueous phase was separated andextracted with DCM (100 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (PE:DCM=5:1) to give the title compound (3.5 g, 85%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃): δ 7.62 (s, 1H), 7.40-7.26 (m, 5H), 6.77(t, J=1.8 Hz, 1H), 6.64 (m, 1H), 4.45 (d, J=5.4 Hz, 2H). LCMS: 325; 327(M+H)+.

Step 2: N-benzyl-5-bromo-3-methylsulfanyl-2-nitroaniline

To a solution of the title compound from step 1 (750 mg, 2.3 mmol) inTHF (20 mL) was added sodium methanethiolate (240 mg, 3.5 mmol). Thereaction mixture was stirred at rt overnight. The mixture was pouredover ice water (30 ml) and extracted with DCM (30 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (PE:DCM=5:1) to give the title compound (300 mg, 37%) as asolid. LCMS: 353; 355 (M+H)⁺.

Step 3: N-benzyl-5-bromo-3-methylsulfonyl-2-nitroaniline

To a solution of the title compound form step 2 (750 mg, 2.1 mmol) inDCM (70 mL) was added 3-chloroperoxybenzoic acid (1.65 mg, 9.6 mmol).The reaction mixture was stirred at RT overnight. The mixture was pouredover ice water (30 ml) and extracted with DCM (30 mL×2). The combinedorganic layers were washed with brine and saturated NaHCO₃ solution (100ml), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (PE:EA=30:1) to give the title compound (820 mg, 85%). ¹H NMR (300MHz, CDCl₃): δ 7.56 (s, 1H), 7.40-7.23 (m, 6H), 6.51 (s, 1H), 4.45 (d,J=4.2 Hz, 2H), 3.44 (s, 3H). LCMS: 402; 404 (M+NH₄)⁺.

Step 4: 1-benzyl-6-bromo-2-methyl-4-methylsulfonylbenzimidazole

The title compound from step 3 (350 mg, 0.9 mmol) was suspended in MeOH(30 mL) and saturated NH₄Cl aqueous solution (10 mL). Iron (300 mg, 5.4mmol) was added and the mixture was heated to 80° C. for 1 hr. Thereaction mixture was then filtered. The filtrate was diluted with H₂Oand extracted with EtOAc (30 mL×2). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was dissolved in 5M HCl (2 mL, 10 mmol) followed by2,4-pentanedione (753 mg, 7.5 mmol) addition. The reaction mixture washeated to 75° C. for 1 hr. After cooling to RT and neutralization with aNaHCO₃ solution, it was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound (260 mg,76%) as a solid. ¹H NMR (300 MHz, CDCl₃): δ 8.01 (s, 1H), 7.62 (s, 1H),7.34-7.26 (m, 3H), 7.07-7.00 (m, 2H), 5.33 (s, 2H), 3.47 (s, 3H), 2.64(s, 3H).

LCMS: 379; 381 (M+H)⁺

Step 5:5-(3-benzyl-2-methyl-7-methylsulfonylbenzimidazol-5-yl)-1,3-dimethylpyridin-2-one

The title compound form step 4 (100 mg, 0.26 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(90 mg, 0.36 mmol), K₂CO₃ (108 mg, 0.78 mmol) and Pd(dppf)Cl₂ (40 mg,0.054 mmol) in a DMF/H₂O mixture (10 mL/1 mL) under N₂ was heated to100° C. for 3 hr. After cooling to RT, addition of water, and EtOAcextractive work up (50 mL×3), the combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on silica gel (EtOAc/MeOH, 15:1) to give thetitle compound (55 mg, 50%). ¹H NMR (300 MHz, CDCl₃): δ 7.92 (s, 1H),7.46-7.41 (m, 3H), 7.36-7.26 (m, 3H), 7.08-7.05 (m, 2H), 5.41 (s, 2H),3.62 (s, 3H), 3.51 (s, 3H), 2.65 (s, 3H), 2.22 (s, 3H).

LCMS: 422 (M+H)⁺.

Example 685-(3-benzyl-7-ethylsulfonyl-2-methylbenzimidazol-5-yl)-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 67 bysubstituting sodium ethanethiolate for sodium methanethiolate in step 2and3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 5. ¹H NMR (300 MHz, CDCl₃): δ 7.92 (s, 1H), 7.42-7.26 (m, 4H),7.13-7.08 (m, 3H), 6.81 (d, J=1.8 Hz, 1H), 5.42 (s, 2H), 3.88 (s, 3H),3.75 (q, J=7.5 Hz, 2H), 3.64 (s, 3H), 2.65 (s, 3H), 1.32 (t, J=7.2 Hz,3H). LCMS: 452 (M+H)⁺.

Example 695-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2-methylbenzimidazol-5-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 67 bysubstituting cyclopropylmethanamine for benzyl amine in step 1 andsodium ethanethiolate for sodium methanethiolate in step 2. ¹H NMR (400MHz, DMSO-d₆): δ 8.14 (s, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H),4.23 (d, J=7.2 Hz, 2H), 3.73-3.68 (m, 2H), 3.56 (s, 3H), 2.70 (s, 3H),2.13 (s, 3H), 1.35-1.32 (m, 1H), 1.09 (t, J=7.2 Hz, 3H), 0.55-0.45 (m,4H). LCMS: 400 (M+H)+.

Example 705-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2-methylbenzimidazol-5-yl]-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 67 bysubstituting cyclopropylmethanamine for benzyl amine in step 1, sodiumethanethiolate for sodium methanethiolate in step 2 and3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (s, 1H), 7.79 (s, 1H), 7.76(d, J=1.6 Hz, 1H), 7.21 (s, 1H), 4.25 (d, J=6.8 Hz, 2H), 3.85 (s, 3H),3.74-3.68 (m, 2H), 3.56 (s, 3H), 2.67 (s, 3H), 1.34-1.32 (m, 1H), 1.11(t, J=7.2 Hz, 3H), 0.54-0.46 (m, 4H). LCMS: 416 (M+H)⁺.

Example 71 5-[3-(cyclopropylmethyl)-2-methyl-7-methylsulfonylbenzimidazol-5-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 67 bysubstituting cyclopropylmethanamine for benzyl amine in step 1. ¹H NMR(400 MHz, DMSO-d₆): δ 8.13 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.79 (s,1H), 4.24 (d, J=7.2 Hz, 2H), 3.56 (s, 3H), 3.52 (s, 3H), 2.68 (s, 3H),2.13 (s, 3H), 1.34-1.31 (m, 1H), 0.53-0.48 (m, 4H). LCMS: 386 (M+H)⁺.

Example 72N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethoxybenzimidazol-4-yl]methanesulfonamideStep 1: 5-bromo-N-(cyclopropylmethyl)-3-fluoro-2-nitroaniline

5-bromo-1,3-difluoro-2-nitrobenzene was converted to the title compoundin a manner similar to Example 67, step 1 except thatcyclopropylmethylamine was substituted for benzylamine.

Step 2:N-[5-bromo-3-(cyclopropylmethylamino)-2-nitrophenyl]methanesulfonamide

To methanesulfonamide (1.32 g, 13.9 mmol) in DMF (40 ml) was addedt-BuOK (1.09 g, 9.7 mmol) at RT. After stirring for 30 min, the titlecompound from step 1 (2.0 g, 6.9 mmol) was added. The mixture wasstirred overnight, poured into ice water (50 ml), adjusted to pH 6-7with acetic acid, and extracted with EA (50 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive a red residue which was then triturated with ether (30 ml). Theyellow solid that remained was dried to give the title compound (1.1 g,44%). ¹H NMR (300 MHz, DMSO-d₆): δ 9.81 (s, 1H), 7.07-7.04 (m, 1H), 6.96(d, J=1.8 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H), 3.14-3.04 (m, 5H), 1.10-1.04(m, 1H), 0.50-0.44 (m, 2H), 0.27-0.21 (m, 2H). LCMS: 364, 366 (M+H⁺).

Step 3:N-[2-amino-5-bromo-3-(cyclopropylmethylamino)phenyl]methanesulfonamide

To the title compound from step 2 (850 mg, 2.34 mmol) in MeOH (30 mL)was added saturated aqueous NH₄Cl (10 mL) and Fe (655 mg, 11.7 mmol).The mixture was heated at 80° C. for 1 hr and then filtered. The solidsremoved by filtration were washed with EA, and water was added to thecombined filtrate and washings. EA extraction (40 mL×2) was carried out,and the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give the title compound (690 mg, 88%) as a yellow solid.LCMS: 334, 336 (M+H⁺).

Step 4:N-[6-bromo-1-(cyclopropylmethyl)-2-ethoxy-benzimidazol-4-yl]methanesulfonamide

To the title compound of step 3 (150 mg, 0.45 mmol) in AcOH (4 mL) wasadded tetraethylorthocarbonate (259 mg, 1.35 mmol). The mixture washeated at 60° C. for 0.5 hr, cooled, diluted with water, neutralizedwith saturated aqueous NaHCO₃, and extracted with EA (30 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated, and purified using silica gel chromatography (PE:EA=2:1)to give the title compound (75 mg, 43%) as a white solid. ¹H NMR (300MHz, DMSO-d₆): δ 9.55 (s, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.12 (d, J=2.1Hz, 1H), 4.57 (q, J=7.2 Hz, 2H), 3.90 (d, J=5.1 Hz, 2H), 3.25 (s, 3H),1.28-1.17 (m, 1H), 1.09 (t, J=6.9 Hz, 3H), 0.52-0.36 (m, 4H). LCMS: 388,390 (M+H⁺).

Step 5:N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethoxybenzimidazol-4-yl]methanesulfonamide

The title compound of step 4 (75 mg, 0.19 mmol),1,3-dimethyl-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(58 mg, 0.23 mmol), K₂CO₃ (79 mg, 0.57 mmol) and Pd(dppf)Cl₂ (15 mg,0.019 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ were heated at 85° C.for 3 hr. The mixture was cooled and filtered, and the filtrate wasdiluted with water and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive a residue which was triturated with EA/ether (3 ml/20 ml). Thewhite solid that remained was dried to give the title compound (48 mg,58%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 7.91 (s, 1H), 7.72 (s,1H), 7.49 (s, 1H), 7.13 (s, 1H), 4.57 (q, J=6.4 Hz, 2H), 3.92 (d, J=6.4Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, J=6.8 Hz,3H), 1.31-1.28 (m, 1H), 0.51-0.42 (m, 4H). LCMS: 431 (M+H⁺).

Example 73N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4-yl]methanesulfonamideStep 1:N-[6-bromo-1-(cyclopropylmethyl)-2-methoxybenzimidazol-4-yl]methanesulfonamide

To the title compound of Example 72, step 3 (200 mg, 0.60 mmol) in AcOH(5 mL) was added tetramethylorthocarbonate (245 mg, 1.8 mmol). Themixture was heated at 60° C. for 0.5 hr, cooled, diluted with water,neutralized with saturated aqueous NaHCO₃, and extracted with EA (40mL×2). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, concentrated and purified using silica gelchromatography (PE:EA=2:1) to give the title compound (130 mg, 58%) as awhite solid. LCMS: 374, 376 (M+H⁺).

Step 2:N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4-yl]methanesulfonamide

The title compound of step 1 (130 mg, 0.35 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(104 mg, 0.41 mmol), K₂CO₃ (145 mg, 1.05 mmol) and Pd(dppf)Cl₂ (26 mg,0.035 mmol) in dioxane/H₂O (12 mL/4 mL) under N₂ were heated at 85° C.for 3 hr. The mixture was cooled and filtered, and the filtrate wasdiluted with water and extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive a residue which was triturated with EA (5 ml). The white solid thatremained was dried to give the title compound (69 mg, 48%). ¹H NMR (400MHz, DMSO-d₆): δ 9.38 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.49 (s, 1H),7.14 (s, 1H), 4.15 (s, 3H), 3.92 (d, J=7.2 Hz, 2H), 3.54 (s, 3H), 3.26(s, 3H), 2.10 (s, 3H), 1.30-1.29 (m, 1H), 0.50-0.41 (m, 4H). LCMS: 417(M+H⁺).

Example 74N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethylbenzimidazol-4-yl]methanesulfonamideStep 1:N-[6-bromo-1-(cyclopropylmethyl)-2-ethylbenzimidazol-4-yl]methanesulfonamide

To the title compound of Example 72, step 3 (150 mg, 0.45 mmol) in AcOH(5 mL) was added triethylorthopropionate (238 mg, 1.35 mmol). Themixture was heated at 60° C. for 0.5 hr, cooled, diluted with water,neutralized with saturated aqueous NaHCO₃, and extracted with EA (20mL×2). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, concentrated and purified using silica gelchromatography (PE:EA=2:1) to give the title compound (80 mg, 48%) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.65 (d, J=1.2 Hz, 1H), 7.15(d, J=1.2 Hz, 1H), 4.10 (d, J=6.6 Hz, 2H), 2.95-2.88 (q, J=7.5 Hz, 2H),2.65 (s, 3H), 1.36 (t, J=7.5 Hz, 3H), 1.23-1.18 (m, 1H), 0.51-0.39 (m,4H). LCMS: 372, 374 (M+H⁺).

Step 2:N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethylbenzimidazol-4-yl]methanesulfonamide

The title compound of step 1 (80 mg, 0.22 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(64 mg, 0.26 mmol), K2CO3 (89 mg, 0.65 mmol) and Pd(dppf)Cl₂ (16 mg,0.022 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ were heated at 85° C.for 3 hr. The mixture was cooled and filtered, and the filtrate wasdiluted with water and extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive a residue which was purified by prep-TLC (DCM:MeOH:20:1) to givethe title compound (23 mg, 25%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.36 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.13(s, 1H), 4.57 (q, J=6.4 Hz, 2H), 3.92 (d, J=6.4 Hz, 2H), 3.54 (s, 3H),3.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, J=6.8 Hz, 3H), 1.31-1.28 (m, 1H),0.51-0.42 (m, 4H) LCMS: 415 (M+H⁺).

Example 755-(1-ethyl-4-methylsulfonylindol-2-yl)-1,3-dimethylpyridin-2-one Step 1:4-methylsulfanyl-1H-indole

To a solution of 4-bromo-1H-indole (8.0 g, 41 mmol) in dry THF (100 mL)was added sodium hydride (50%, 3.6 g, 90 mmol) at 0° C. Twenty minuteslater, the reaction mixture was cooled to −78° C. and t-BuLi (1.3 M inTHF, 63 mL) was added dropwise under nitrogen. After thirty min, asolution of dimethyl disulfide (7.7 g, 82 mmol) in THF (10 mL) was addeddrop wise at −78° C. Thirty min later, the reaction was poured over icewater (100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography (EtOAc/petroleum ether,0-10%) to give the title product (3.7 g, 56%). ¹H NMR (CDCl₃, 300 MHz):δ 8.25 (brs, 1H), 7.26-7.24 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 7.02 (d,J=7.5 Hz, 1H), 6.69 (m, 1H), 2.59 (s, 3H). LCMS: 164 (M+H)⁺.

Step 2: 1-(benzenesulfonyl)-4-methylsulfanylindole

To a solution of the title compound from step 1 (3.6 g, 22 mmol) in dryDMF (100 mL) cooled with an ice bath was added NaH (60%, 1.3 g, 33mmol). The mixture was stirred for thirty min. Benzenesulfonyl chloride(5.8 g, 33 mmol) was added drop wise at 0° C. and the reaction wasstirred for 2 hr. After this time, the mixture was poured over ice waterand filtered to give the title compound as a yellow solid (4.6 g, 70%).¹H NMR (CDCl₃, 300 MHz): δ 8.05 (d, J=8.1 Hz, 1H), 7.87 (m, 2H), 7.81(d, J=8.1 Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 7.43 (m, 2H), 7.26 (t, J=3.9Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 2.51 (s, 3H).LCMS: 304 (M+H)⁺.

Step 3: 1-(benzenesulfonyl)-2-bromo-4-methylsulfanylindole

To a solution of the title compounds from step 2 (1.6 g, 5.2 mmol) indry THF (20 mL) was added LDA (2.0 M in THF, 3.9 mL, 7.8 mmol) undernitrogen at −78° C. The reaction was stirred for 30 min. A solution of1,2-dibromo-1,1,2,2-tetrachloroethane (2.6 g, 7.9 mmol) in dry THF (10mL) was added drop wise at the same temperature over 20 min and thereaction was stirred for 1 hr. The mixture was slowly poured overaqueous NH₄Cl (50 mL) cooled with an ice bath. It was extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate, 5:1) to give the titleproduct as a white solid (1.3 g, 65%). ¹H NMR (CDCl₃, 400 MHz): δ 8.09(d, J=8.8 Hz, 1H), 7.89 (m, 2H), 7.56 (m, 1H), 7.44 (m, 2H), 7.28 (m,1H), 7.11 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 2.50 (s, 3H). LCMS: 382; 384(M+H)⁺.

Step 4: 1-(benzenesulfonyl)-2-bromo-4-methylsulfonylindole

A solution of the title compound from step 3 (1.3 g, 4.3 mmol) and3-chloroperoxybenzoic acid (85%, 2.2 g, 11 mmol) in dichloromethane (30mL) was stirred at RT for 1 hr followed by addition of saturated aqueousNaHSO₃ (30 mL). The organic layer was separated and washed withsaturated sodium hydrogen carbonate, dried over sodium sulfate, filteredand concentrated under reduced pressure to give the title compound as awhite solid (1.17 g, 66%). ¹H NMR (CDCl₃, 300 MHz): δ 8.60 (d, J=8.4 Hz,1H), 7.94-7.86 (m, 3H), 7.64 (t, J=7.2 Hz, 1H), 7.52-7.47 (m, 3H), 7.31(s, 1H), 3.06 (s, 3H). LCMS: 431; 433 (M+NH₄)⁺.

Step 5: 2-bromo-4-methylsulfonyl-1H-indole

To a solution of title compound from step 4 (1.17 g, 2.8 mmol) in THF(30 mL) was added sodium hydroxide (124 mg, 3.1 mmol). The mixture wasrefluxed for 1 hr. The solvent was removed under reduced pressure andthe residue was dissolved in ethyl acetate (30 mL). The organic layerwas washed with saturated sodium hydrogen carbonate, dried over sodiumsulfate, filtered and concentrated under reduced pressure to give thetitle compound as solid (550 mg, 71%). ¹H NMR (CDCl₃, 300 MHz): δ 7.75(d, J=7.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.04(s, 1H), 3.11 (s, 3H). LCMS: 274; 276 (M+H)⁺.

Step 6: 2-bromo-1-ethyl-4-methylsulfonylindole

A mixture of the title compound from step 5 (200 mg, 0.7 mmol),iodoethane (125 mg, 0.8 mmol) and potassium carbonate (300 mg, 2.17mmol) in DMF (5 mL) was stirred at RT for 2 hr. Water (50 mL) and ethylacetate (50 mL) were added. The organic layer was separated and washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative TLC (petroleumether/ethyl acetate, 3:1) to give the title compound (147 mg, 67%). ¹HNMR (CDCl₃, 300 MHz): δ 7.68 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.25 (t, J=8.0 Hz, 1H), 7.00 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.04 (s,3H), 1.317 (t, J=7.2 Hz, 3H). LCMS: 302; 304 (M+H)⁺.

Step 7: 5-(1-ethyl-4-methylsulfonylindol-2-yl)-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 1, step2, by substituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-oneand 2-bromo-1-ethyl-4-methylsulfonylindole for6-bromo-2-methyl-3H-1,2-benzothiazole 1,1-dioxide. ¹H NMR (DMSO-d6, 400MHz): δ 7.94 (m, 2H), 7.61 (d, J=7.4 Hz, 1H), 7.58 (s, 1H), 7.37 (m,1H), 6.81 (s, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.54 (s, 3H), 3.20 (s, 3H),2.10 (s, 3H), 1.23 (t, J=6.8 Hz, 3H). LCMS: 345.05 (M+H)⁺.

Example 765-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 75 bysubstituting bromomethylcyclopropane for iodoethane in step 6. ¹H NMR(DMSO-d6, 400 MHz): δ 8.0 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.61 (m, 2H),7.36 (m, 1H), 6.82 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.54 (s, 3H), 3.22(s, 3H), 2.10 (s, 3H), 0.99 (m, 1H), 0.37 (m, 2H), 0.21 (m, 2H). LCMS:371.05 (M+H)⁺.

Example 775-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 75 bysubstituting 2-iodoethylcyclopropane for iodoethane in step 6. ¹H NMR(DMSO-d6, 400 MHz): δ 7.95 (m, 2H), 7.60 (m, 2H), 7.36 (m, 1H), 6.81 (s,1H), 4.35 (m, 2H), 3.54 (s, 3H), 3.20 (s, 3H), 2.10 (s, 3H), 1.51 (m,2H), 0.44 (m, 1H), 0.26 (m, 2H), −0.12 (m, 2H). LCMS: 385.1 (M+H)⁺.

Example 784-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 76 bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.¹H NMR (DMSO-d6, 400 MHz) 8.34 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.3 Hz,1H), 7.83 (s, 1H), 7.68 (m, 2H), 7.57 (m, 1H), 7.43 (t, J=8.1 Hz, 1H),7.21 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 4.21 (m, 1H), 3.78 (m, 1H), 3.61(s, 3H), 3.24 (s, 3H), 0.95 (m, 1H), 0.29 (m, 2H), 0.10 (m, 2H). LCMS:407.05 (M+H)⁺.

Example 79N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]methanesulfonamideStep 1: 2-cyclopropyl-7-iodo-5-nitro-1-benzofuran

A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol),ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu₂O (1.9 mg, 13.2 mmol) in100 mL of dry pyridine was refluxed for 2 hr. The reaction mixture waspoured into 1 L of water and stirred for 10 min. The resulting mixturewas filtered. The cake was purified by column chromatography on silicagel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78%yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=2.4 Hz,1H), 8.32 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04(m, 4H).

Step 2:4-(2-cyclopropyl-5-nitro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

To a mixture of 2-cyclopropyl-7-iodo-5-nitro-1-benzofuran (200 mg, 0.61mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(101 mg, 0.67 mmol) and Na₂CO₃ (120 mg, 1.22 mmol) in DMF/H₂O (12 mL/3mL) under N₂ was added Pd(dppf)Cl₂ (23 mg). The reaction mixture washeated to 100° C. for 1 hr. Water (30 mL) and ethyl acetate (30 mL) wereadded. The organic layer was separated, washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 4:1) to afford the title compound (127 mg, 58%yield).

LCMS: 378 (M+18)⁺.

Step 3:4-(5-amino-2-cyclopropyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 32, step2, by substituting4-(2-cyclopropyl-5-nitro-1-benzofuran-7-yl)-2-methylisoquinolin-1-onefor 6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole. LCMS: 331(M+18)⁺.

Step 4:N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]methanesulfonamide

To a solution of the title compound from step 3 (100 mg, 0.30 mmol) andpyridine (64 mg, 0.90 mmol) in dichloromethane (10 mL) was addedmethanesulfonyl chloride (34 mg, 0.30 mmol) at rt. The reaction wasstirred for 1.5 hr. It was diluted with dichloromethane (30 mL) andwashed with 1 N HCl (10 mL), water and brine. The organic phase wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative TLC (EtOAc) to givethe title compound (12.6 mg, 10%). ¹H NMR (CDCl₃, 400 MHz): δ 8.47 (d,J=7.6 Hz, 1H), 7.52-7.43 (m, 2H), 7.35 (d, J=1.6 Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.14 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.43 (s, 1H), 6.32 (s,1H), 3.61 (s, 3H), 2.96 (s, 3H), 1.81-1.85 (m, 1H), 0.89-0.79 (m, 2H),0.74-0.71 (m, 2H). LCMS: 409 (M+1)⁺.

Example 80N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1-benzofuran-5-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 79 bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onein step 2. ¹H NMR (CDCl₃, 300 MHz): δ 8.08 (d, J=2.1 Hz, 1H), 7.90 (s,1H), 7.34 (d, J=2.1 Hz, 1H), 7.20 (d, J=1.8 Hz, 1H), 6.50 (s, 1H), 3.70(s, 3H), 2.95 (s, 3H), 2.24 (s, 3H), 2.17-2.11 (m, 1H), 1.11-0.94 (m,4H).

LCMS: 373 (M+1)⁺.

Example 81N-[9-(cyclopropylmethyl)-2-(1,5-dimethyl-6-oxopyridin-3-yl)-8-methylpurin-6-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 22 bysubstituting bromomethylcyclopropane for1-(bromomethyl)-4-fluoro-benzene in step 1. ¹H NMR (400 MHz, DMSO-d₆): δ8.46 (s, 1H), 8.19 (s, 1H), 4.13 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.55(s, 3H), 2.63 (s, 3H), 2.11 (s, 3H), 1.34-1.31 (m, 1H), 0.52-0.50 (m,4H). LCMS: 403 [M+H].

Example 82N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 79 bysubstituting ethanesulfonyl chloride for methanesulfonyl chloride. ¹HNMR (CDCl₃, 300 MHz): δ 8.57 (d, J=7.8 Hz, 1H), 7.61-7.51 (m, 2H), 7.43(s, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.07 (s, 1H), 6.44 (brs,1H), 6.41 (s, 1H), 3.70 (s, 3H), 3.19 (q, J=7.5 Hz, 2H), 2.01-1.92 (m,1H), 1.43 (t, J=7.5 Hz, 3H), 0.95-0.91 (m, 2H), 0.81-0.78 (m, 2H). LCMS:423 (M+1)⁺.

Example 83N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-phenyl-1-benzofuran-5-yl]methane-sulfonamideStep 1: 7-iodo-5-nitro-2-phenyl-1-benzofuran

To a solution of 2,6-diiodo-4-nitrophenol (1.0 g, 2.6 mmol) andethynylbenzene (265 mg, 2.6 mmol) in pyridine (15 mL) was added Cu₂O(186 mg, 1.3 mmol). The mixture was refluxed under N₂ overnight. Thesolvent was removed under reduced pressure and the residue waspartitioned between water (20 mL) and ethyl acetate (30 mL). The organiclayer was separated and washed with brine, dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel (EtOAc/PE, 0-20%) to give the titlecompound (0.6 g, 63%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.60(d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.78(s, 1H), 7.60-7.51 (m, 3H).

Step 2: 7-iodo-2-phenyl-1-benzofuran-5-amine

To a mixture of the title compound from step 1 (400 mg, 1.1 mmol) and Fe(184 mg, 3.3 mmol) in methanol (5 mL) was added saturated aqueous NH₄Cl(176 mg, 3.3 mmol) and water (2 mL). The reaction was refluxed for 30min. Solvents were removed under reduced pressure. The residue waspartitioned between water (10 mL) and ethyl acetate (10 mL) followed byfiltration. The organic phase was separated, dried over sodium sulfate,filtered and concentrated under reduced pressure to give the titlecompound (154 mg, 42%) as a solid that was used in the next step withoutfurther purification. LCMS: 336 (M+1)⁺.

Step 3: N-(7-iodo-2-phenyl-1-benzofuran-5-yl)methanesulfonamide

The title compound was prepared in a manner similar to Example 79, step4, by substituting 7-iodo-2-phenyl-1-benzofuran-5-amine for4-(5-amino-2-cyclopropyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one.¹H NMR (CDCl₃, 400 MHz): δ 7.88 (d, J=7.2 Hz, 2H), 7.52-7.41 (m, 5H),7.09 (s, 1H), 6.52 (brs, 1H), 3.02 (s, 3H).

Step 4:N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-phenyl-1-benzofuran-5-yl]methanesulfonamide

To a mixture of the title compound from step 3 (30 mg, 0.09 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(27 mg, 0.11 mmol) and KOAc (27 mg, 0.28 mmol) in DMF (3 mL) was addeddichloro[1,1′-bis(di-tert-butylphos-phino)ferrocene]palladiumII (3 mg)under N₂. The reaction was heated at 100° C. for 3 hr. Water (30 mL) wasadded and the resulting mixture was filtered. The cake was purified bypreparative TLC (ethyl acetate/petroleum ether=2:1) to give the titlecompound (15 mg, 41%). ¹H NMR (CD₃OD, 400 MHz): δ 8.25 (d, J=1.2 Hz,1H), 8.02 (s, 1H), 7.94-7.92 (m, 2H), 7.54-7.51 (m, 3H), 7.45-7.43 (d,J=7.2 Hz, 1H), 7.33-7.32 (d, J=2.4 Hz, 1H), 7.29 (s, 1H), 3.77 (s, 3H),3.01 (s, 3H), 2.29 (s, 3H).

LCMS: 409 (M+1)⁺.

Example 84N-[7-(2-methyl-1-oxoisoquinolin-4-yl)-2-phenyl-1-benzofuran-5-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 83 bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 4. ¹H NMR (CD₃OD, 400 MHz): δ 8.51 (d, J=7.2 Hz, 1H), 7.71-7.61(m, 6H), 7.47 (d, J=8.0 Hz, 1H), 7.39-7.34 (m, 3H), 7.31 (s, 1H), 7.28(d, J=2.4 Hz, 1H), 3.76 (s, 3H), 3.05 (s, 3H). LCMS: 445 (M+1)⁺.

Example 858-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2,3-dihydro-1H-indolizin-5-oneStep 1: methyl 6-methyl-5-oxo-2,3-dihydro-1H-indolizine-8-carboxylate

To methyl 5-oxo-6-((trifluoromethyl)sulfonyloxy)-1,2,3-trihydroindolizine-8-carboxylate (170 mg, 0.50 mmol),prepared as described previously (Padwa et al., 64 J. Org. Chem. 8648(1999)), Pd(dppf)Cl₂ (7 mg, 0.01 mmol), and Na₂CO₃ (105 mg, 1 mmol) inTHF (2 mL) was added methylboronic acid (45 mg, 0.75 mmol) at RT underN₂. The mixture was stirred at 80° C. for 12 hr, cooled, concentrated,and purified using silica gel chromatography (PE:EA=10:1 to 5:1) to givethe title compound (90 mg, 87% yield) as a yellow solid. ¹H NMR (CDCl₃,400 MHz) δ 7.77 (s, 1H), 4.18 (t, J=7.6 Hz, 2H), 3.85 (s, 3H), 3.52 (d,J=7.6 Hz, 2H), 2.24 (d, J=7.6 Hz, 2H), 2.15 (s, 3H). LCMS: 208 (M+H⁺).

Step 2: 6-methyl-2,3-dihydro-1H-indolizin-5-one

The title compound of step 1 (60 mg, 0.29 mmol) in aqueous 48% HBr (4mL) was stirred at 170° C. for 24 hr. The mixture was cooled and thevolatile components removed under vacuum to give the title compound (40mg) as a yellow solid which was carried on without purification. LCMS:150 (M+H⁺).

Step 3: 8-bromo-6-methyl-2,3-dihydro-1H-indolizin-5-one

To the title compound of step 2 (combined with material from earlierpreparations) (220 mg, 1.47 mmol) in MeCN (5 mL) was added NBS (262 mg,1.47 mmol) at RT under N₂. The mixture was stirred at RT for 3 hr,concentrated, diluted with water, and extracted with DCM (20 mL×2). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated to dryness to afford the titlecompound (300 mg, 89% yield) as gray solid which was carried withoutpurification. ¹H NMR (DMSO, 400 MHz) δ 7.36 (s, 1H), 3.96 (t, J=8.0 Hz,2H), 2.97 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.06 (m, 2H).

Step 4:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2,3-dihydro-1H-indolizin-5-one

To the title compound of step 3 (50 mg, 0.22 mmol) and2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(78 mg, 0.22 mmol) in dioxane (4 mL) and H₂O (0.4 mL) was addedPd(dppf)Cl₂ (8 mg, 0.01 mmol) and K₃PO₄ (103 mg, 0.49 mmol) at RT underN₂. The mixture was stirred at 90° C. for 12 hr, cooled, concentrated,and purified using silica gel chromatography (PE:EA=1:1˜0:1) followed bypreparative HPLC to give the title compound (15 mg, 37% yield) as awhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (q, J=6.4 Hz, 1H), 7.75 (t,J=2.4 Hz, 1H), 7.34 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.30 (t, J=7.2 Hz,2H), 3.91 (d, J=6.8 Hz, 2H), 3.07 (s, 3H), 3.03 (t, J=7.6 Hz, 2H),2.17-2.22 (m, 5H), 1.20-1.26 (m, 1H), 0.63-0.68 (m, 2H), 0.33 (d, J=4.8Hz, 2H). LCMS: 374 (M+H⁺).

Example 86N-[4-(2,4-difluorophenoxy)-3-(6-methyl-5-oxo-2,3-dihydro-1H-indolizin-8-yl)phenyl]methanesulfonamide

To the title compound of Example 85, step 3 (40 mg, 0.18 mmol) andN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide(111 mg, 0.26 mmol) in 1,4-dioxane (3 mL) and H₂O (0.3 mL) was addedK₃PO₄ (74 mg, 0.35 mmol) and Pd(dppf)Cl₂ (6 mg, 0.01 mmol) at RT underN₂. The mixture was stirred at 90° C. for 12 hr, cooled, concentrated,and purified by silica gel chromatography (PE:EA=1:1˜0:1) followed bypreparative HPLC to give the title compound (27.26 mg, 38% yield) as awhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.39 (s, 1H), 7.20 (d, J=2.4 Hz,1H), 7.15 (dd, J₁=2.8 Hz, J₂=8.8 Hz, 1H), 6.91-6.98 (m, 2H), 6.75-6.87(m, 2H), 4.31 (t, J=7.2 Hz, 2H), 3.12 (t, J=8 Hz, 2H), 3.05 (s, 3H),2.23 (t, J=7.2 Hz, 2H), 2.19 (s, 3H). LCMS: 447 (M+H⁺).

Example 878-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,2,6-trimethyl-1,3-dihydroindolizin-5-oneStep 1: 1-[2-(benzenesulfonyl)acetyl]-4,4-dimethylpyrrolidin-2-one

To phenylsulfonylacetic acid (9.50 g, 47.45 mmol) in toluene (80 mL) wasadded (COCl)₂ (6.02 g, 47.45 mmol) containing DMF (0.3 g, 4.75 mmol) at20° C. under N₂. The mixture was stirred at 20° C. for 1 hr and thenconcentrated under vacuum to remove excess (COCl)₂. Toluene (80 ml) wasadded to the residue/crude acid chloride, and this solution was added to4,4-dimethylpyrrolidin-2-one (4.30 g, 37.96 mmol) in toluene (80 ml).The mixture was refluxed for 8 hr, cooled, concentrated, diluted withwater and extracted with EA (100 mL×3). The combined organic layers werewashed with brine (80 mL), dried over Na₂SO₄, filtered, concentrated,and purified using silica gel chromatography (PE:EA=5:1˜1:1) to give thetitle compound (11 g, 78% yield) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.97 (d, J=7.2 Hz, 2H), 7.68 (t, J=8.0 Hz, 1H), 7.58 (t, J=8.0Hz, 2H), 4.97 (s, 2H), 3.54 (s, 2H), 2.41 (s, 2H), 1.17 (s, 6H).

Step 2:1-[2-(benzenesulfonyl)-2-diazoacetyl]-4,4-dimethylpyrrolidin-2-one

The title compound of step 1 (10 g, 33.86 mmol) and Et₃N (8.76 g, 86.57mmol) in CH₃CN (100 mL) were stirred at 0° C. under N₂. After 30 min,p-acetamidophenylsulfonyl azide (10 g, 41.63 mmol) was added. Themixture was warmed to RT and stirred for 12 hr, then concentrated,diluted with water, and extracted with DCM (120 ml×3). The combinedorganic layers were dried with Na₂SO₄, filtered, concentrated, andpurified using silica gel chromatography (PE:EA=5:1˜3:1) to give thetitle compound (9 g, 82% yield) as a yellow solid. ¹H NMR (CDCl₃, 400MHz) δ 8.08 (d, J=7.6 Hz, 2H), 7.66 (t, J=7.2 Hz, 1H), 7.57 (t, J=7.6Hz, 2H), 3.48 (s, 2H), 2.38 (s, 2H), 1.15 (s, 6H).

Step 3: methyl6-hydroxy-2,2-dimethyl-5-oxo-1,3-dihydroindolizine-8-carboxylate

To the title compound of step 2 (5.00 g, 15.56 mmol) and methyl acrylate(6.70 g, 77.80 mmol) in toluene (100 mL) was added Rh₂ (OAc)₄ (69 mg,155.6 umol) at RT under N₂. The mixture was refluxed for 3 hr, cooled,concentrated, diluted with water, and extracted with EA (100 mL×3). Thecombined organic layers were washed with brine (50 mL×2), dried overNa₂SO₄, filtered, concentrated, and purified using silica gelchromatography (PE:EA=3:1˜1:1) to give the title compound (1.50 g, 41%yield) as a yellow solid.

Step 4: methyl2,2-dimethyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,3-dihydroindolizine-8-carboxylate

To the title compound of step 3 (1.50 g, 6.32 mmol) in DCM (30 mL) wasadded N-phenylbis(trifluoromethanesulfonamide) (4.52 g, 12.64 mmol) andEt₃N (1.28 g, 12.64 mmol) at RT under N₂. The mixture was stirred at RTfor 3 hr, diluted with water, and extracted with DCM (50 ml×2). Thecombined organic layers were concentrated and purified using silica gelchromatography (PE:EA=10:1˜5:1) to give the title compound (1 g, 42%yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (s, 1H), 3.98(s, 2H), 3.88 (s, 3H), 3.37 (s, 2H), 1.26 (s, 6H). LCMS: 370 (M+H⁺).

Step 5: methyl 2,26-trimethyl-5-oxo-1,3-dihydroindolizine-8-carboxylate

To the title compound of step 4 (170 mg, 0.46 mmol) in THF (5 mL) andH₂O (0.5 mL) was added methylboronic acid (90 mg, 1.5 mmol), Na₂CO₃ (106mg, 1 mmol), and Pd(dppf)Cl₂ (8 mg, 0.01 mmol) at RT under N₂. Themixture was stirred at 80° C. for 12 hr, cooled, concentrated, andpurified using silica gel chromatography (PE:EA=10:1) to give the titlecompound (40 mg, 37% yield) as yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ7.75 (s, 1H), 3.90 (s, 2H), 3.85 (s, 3H), 3.29 (s, 2H), 2.15 (s, 3H),1.23 (s, 6H). LCMS: 236 (M+H⁺).

Step 6: 2,2,6-trimethyl-1,3-dihydroindolizin-5-one

The title compound of step 5 (250 mg, 1.21 mmol) in aqueous 48% HBr (5mL) was stirred at 170 C.° for 24 hr. The mixture was cooled and thevolatile components removed under vacuum at 45° C. to give the titlecompound (160 mg) as a yellow solid which was carried on withoutpurification. LCMS: 178 (M+H⁺).

Step 7: 8-bromo-2,2,6-trimethyl-1,3-dihydroindolizin-5-one

To the title compound from step 6 (30 mg, 0.17 mmol) in MeCN (2 mL) wasadded NBS (30 mg, 0.17 mmol) at RT under N₂. The mixture was stirred atRT for 1 hr, diluted with water and extracted with EA (20 ml×2). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give the title compound (30 mg, 77% yield) as yellowsolid which was carried on without purification. LCMS: 256, 258 (M+H⁺).

Step 8:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,2,6-trimethyl-1,3-dihydroindolizin-5-one

To the title compound of step 7 (35 mg, 0.14 mmol) and2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(48 mg, 0.14 mmol) in 1,4-dioxane (3 mL) and H₂O (0.3 mL) was addedK₃PO₄ (58 mg, 0.27 mmol), and Pd(dppf)Cl₂ (5 mg, 0.01 mmol) at RT underN₂. The mixture was stirred at 90° C. for 12 hr, cooled, concentrated,and purified using silica gel chromatography (PE:EA=1:1˜0:1) followed bypreparative HPLC to give the title compound (20 mg, 36% yield) as awhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (q, J=6.4 Hz, 1H), 7.73 (d,J=2.4 Hz, 1H), 7.29 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.00 (s, 2H), 3.91(d, J=7.2 Hz, 2H), 3.08 (s, 3H), 2.79 (s, 2H), 2.20 (s, 3H), 1.24 (m,1H), 1.20 (s, 6H), 0.64 (m, 2H), 0.31 (q, J=5.6 Hz, 2H). LCMS: 402(M+H⁺).

Example 88N-[4-(2,4-difluorophenoxy)-3-(2,2,6-trimethyl-5-oxo-1,3-dihydroindolizin-8-yl)phenyl]methanesulfonamide

To the title compound of Example 87, step 7 (50 mg, 0.20 mmol) andN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide(125 mg, 0.29 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was addedK₃PO₄ (82 mg, 0.39 mmol) and Pd(dppf)Cl₂ (7 mg, 0.01 mmol) at RT underN₂. The mixture was stirred at 90° C. for 12 hr, and then cooled,concentrated, and purified using silica gel chromatography (PE:EA=1:1)followed by preparative HPLC to give the title compound (10 mg, 11%yield) as a brown solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (s, 1H),7.13-7.16 (m, 2H), 6.90 (q, J=6.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.48(s, 1H), 3.96 (s, 2H), 3.05 (s, 3H), 2.85 (s, 2H), 2.17 (s, 3H), 1.17(s, 6H). LCMS: 475 (M+H⁺).

Example 898-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,1-difluoro-6-methyl-2,3-dihydroindolizin-5-oneStep 1: tert-butyl 1-hydroxy-6-methyl-5-oxo-3H-indolizine-2-carboxylate

Using modifications of procedures described previously (Henegar &Baughman, 40 J. Heterocyclic Chem. 601 (2003)), methyl5-methyl-6-oxo-1H-pyridine-2-carboxylate (1.0 g, 6.0 mmol), Cs₂CO₃ (3.9g, 12 mmol) and t-butyl acrylate (7.7 g, 60 mmol) in DMSO (50 mL) wereheated at 65° C. for 3 hr. The mixture was cooled to 0° C. and 0.5 M HCl(60 mL) was added such that the internal temperature remained <15° C.The resulting solid was collected and washed with PE and then dissolvedin DCM. After washing with brine, the organic layer was separated,dried, filtered, and concentrated to dryness under vacuum to give thetitle compound (1.4 g, 88%) as a white solid which was carried onwithout purification. ¹H NMR (300 MHz, CDCl₃): δ7.38 (d, =7.2 Hz, 1H),6.57 (d, J=7.2 Hz, 1H), 4.63 (s, 2H), 2.24 (s, 3H), 1.56 (s, 9H). LCMS:264 (M+H⁺).

Step 2: 6-methyl-2,3-dihydroindolizine-1,5-dione

The title compound of step 1 (250 mg, 0.95 mmol) and TFA (0.45 mL) intoluene (18 mL) were heated at 75° C. for 24 hr. After cooling, thevolatile components were removed under vacuum. Toluene (20 mL) wasadded, and again the volatile components were removed under vacuum.Purification using silica gel chromatography (PE/EA 1:1) gave the titlecompound (130 mg, 84%) as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ 7.42(d, J=6.8 Hz, 1H), 6.83 (d, J=6.8 Hz, 1H), 4.31 (t, J=6.8 Hz, 2H), 2.90(t, J=6.8 Hz, 2H), 2.27 (s, 3H). LCMS: 164 (M+H⁺).

Step 3: 1,1-difluoro-6-methyl-2,3-dihydroindolizin-5-one

To the title compound of step 2 (150 mg, 0.92 mmol) in DCM (10 mL) wasadded DAST (1.09 mL, 9.2 mmol). The mixture was stirred at RT for 24 hrand then poured onto ice and saturated aqueous NaHCO₃ (30 mL). DCMextractive work up (40 mL×2) gave a residue which was purified usingpreparative TLC (PE:EA 3:1) to give the title compound (68.0 mg, 40%) asa brown oil. ¹H NMR (400 MHz, CDCl₃): δ 7.34 (d, J=6.8 Hz, 1H),6.49-6.43 (m, 1H), 4.21 (t, J=6.8 Hz, 2H), 2.76-2.64 (m, 2H), 2.20 (s,3H). LCMS: 186 (M+H⁺).

Step 4: 8-bromo-1,1-difluoro-6-methyl-2,3-dihydroindolizin-5-one

A solution of 1M bromine in AcOH (0.38 mL) was added slowly to the titlecompound of step 3 (68 mg, 0.37 mmol) in AcOH (3 mL). The mixture wasstirred at RT for 1.5 hr and then poured into water. DCM extractive workup (40 mL×2) gave a residue which was purified using preparative TLC(PE/EA 1:1) to give the title compound (70.0 mg, 72%) as a brown oil. ¹HNMR (300 MHz, CDCl₃): δ 7.40 (s, 1H), 4.23-4.16 (m, 2H), 2.86-2.69 (m,2H), 2.23-2.19 (m, 3H).

Step 5:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,1-difluoro-6-methyl-2,3-dihydroindolizin-5-one

The title compound of step 4 (40 mg, 0.152 mmol),2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(64 mg, 0.18 mmol), K₂CO₃ (63 mg, 0.46 mmol) and Pd(dppf)Cl₂ (11.1 mg,0.015 mmol) in DMF/H₂O (2 mL/0.5 mL) were N₂ purged and microwaved at120° C. for 2 hr. Filtration and DCM extractive work up of the filtrategave a residue that was purified using preparative HPLC to give thetitle compound (17 mg, 27%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ7.92 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.34 (s, 1H),7.03 (d, J=9.2 Hz, 1H), 4.32-4.21 (m, 2H), 3.92 (d, J=6.8 Hz, 2H), 3.04(s, 3H), 2.75-2.62 (m, 2H), 2.24 (s, 3H), 1.20-1.17 (m, 1H), 0.62-0.57(m, 2H), 0.33-0.27 (m, 2H). LCMS: 410 (M+H⁺).

Example 90(±)-8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-fluoro-6-methyl-2,3-dihydro-1H-indolizin-5-oneStep 1: (±)-1-hydroxy-6-methyl-2,3-dihydro-1H-indolizin-5-one

The title compound of Example 89, step 2 (150 mg, 0.92 mmol) was addedto a stirred suspension of NaBH₄ (175 mg, 4.6 mmol) in MeOH (15 mL) atRT. The mixture generated heat and gave a clear solution. Within a fewminutes, water and DCM were added. DCM extractive work up (10 mL×6) gavethe racemic title compound (120 mg, 79%) as a colorless oil which wascarried on without purification. LCMS: 166 (M+H⁺).

Step 2: (±)-1-fluoro-6-methyl-2,3-dihydro-1H-indolizin-5-one

To the title compound of step 1 (120 mg, 0.73 mmol) in DCM (10 mL) wasadded DAST (1.0 mL, 7.3 mmol). The mixture was stirred at RT overnightand then poured onto ice and saturated aqueous NaHCO₃ (30 mL). DCMextractive work up (40 mL×2) gave a residue that was purified usingpreparative TLC (PE/EA 3:1) to give the racemic title compound (100 mg,82%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 7.28-7.30 (m, 1H), 6.38(dd, J=6.8, 4.4 Hz, 1H), 5.81 (ddd, J=55.6, 5.2, 2.8 Hz, 1H), 4.34-4.17(m, 2H), 2.54-2.39 (m, 2H), 2.18 (d, J=3.6 Hz, 3H).

Step 3: (±)-8-bromo-1-fluoro-6-methyl-2,3-dihydro-1H-indolizin-5-one

A solution of 1M bromine in AcOH (0.62 mL) was added slowly to the titlecompound of step 2 (100 mg, 0.60 mmol) in AcOH (3 mL). The mixture wasstirred at RT for 1.5 hr and then poured into water. DCM extractive workup (40 mL×2) gave a residue that was purified using preparative TLC(PE/EA 1:1) to give the racemic title compound (100 mg, 68%) as a brownoil. ¹H NMR (400 MHz, CDCl₃): δ 7.36 (s, 1H), 6.05-5.84 (m, 1H),4.51-4.18 (m, 2H), 2.64-2.32 (m, 2H), 2.19 (d, J=3.6 Hz, 3H). LCMS: 246,248 (M+H⁺).

Step 4:(±)-8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-fluoro-6-methyl-2,3-dihydro-1H-indolizin-5-one

The title compound of step 3 (50 mg, 0.20 mmol),2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(86 mg, 0.25 mmol), K₂CO₃ (85 mg, 0.61 mmol) and Pd(dppf)Cl₂ (15 mg,0.02 mmol) in DMF/H₂O (2 mL/0.5 mL) were N₂ purged and microwaved at120° C. for 2 hr. Filtration and DCM extractive work up of the filtrategave a residue that was purified using preparative HPLC to give theracemic title compound (26 mg, 33%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.95-7.85 (m, 2H), 7.37 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.71(dd, J=58.4 Hz, 5.2 Hz, 1H), 4.42-4.21 (m, 2H), 3.92 (d, J=6.8 Hz, 2H),3.06 (s, 3H), 2.55-2.32 (m, 2H), 2.23 (d, J=2.8 Hz, 3H), 1.25-1.15 (m,1H), 0.65-0.57 (m, 2H), 0.33-0.29 (m, 2H). LCMS: 392 (M+H⁺).

Example 915-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 75 bysubstituting 2-iodoethylcyclopropane for iodoethane in step 6 and3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 7. ¹H NMR (DMSO-d6, 400 MHz): δ 7.96 (d, J=8.1 Hz, 1H), 7.65 (s,1H), 7.61 (d, J=6.9 Hz, 1H), 7.37 (m, 1H), 7.02 (s, 1H), 6.84 (s, 1H),4.37 (m, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 3.21 (s, 3H), 1.52 (m, 2H),0.45 (m, 1H), 0.25 (m, 2H), −0.13 (m, 2H). LCMS: 401.1 (M+H)⁺.

Example 92N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamideStep 1: N-[6-bromo-1-(cyclopropylmethyl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide

Trifluoroacetic anhydride (160 mg, 0.75 mmol) in toluene (2 mL) wasadded dropwise to the title compound of Example 72, step 3 (250 mg, 0.75mmol) in toluene (12 mL) at ice bath temperature. After warming to RTand stirring for 2 hr, the mixture was heated to 90° C. for 2 hr, cooledto RT, neutralized with aqueous saturated NaHCO₃ at ice bathtemperature, and extracted with EtOAc (40 mL×2). The combined extractswere washed with brine, dried over Na₂SO₄, concentrated, and purifiedusing silica gel chromatography (PE/EtOAc=10:1) to give the titlecompound (150 mg, 49%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.22 (s, 1H), 7.97 (s, 1H), 7.40 (s, 1H), 4.32 (d, J=7.2 Hz, 2H), 3.28(s, 3H), 1.27-1.24 (m, 1H), 0.56-0.45 (m, 4H). LCMS: 412, 414 (M+H⁺).

Step 2:N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide

The title compound of step 1 (130 mg, 0.32 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(94 mg, 0.38 mmol), K₂CO₃ (133 mg, 0.96 mmol) and Pd(dppf)Cl₂ (24 mg,0.032 mmol) in dioxane/H₂O (12 mL/4 mL) under N₂ were heated at 85° C.for 3 hr. After cooling to RT, the mixture was filtered, rinsing withEtOAC. The combined filtrate/rinse was diluted with water. Afterextraction with EtOAc (50 mL×3), the combined extracts were dried overNa₂SO₄, filtered, concentrated, and the residue was purified by prep-TLC(EtOAc) to give the title compound (74 mg, 51%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.79 (s,1H), 7.41 (s, 1H), 4.36 (d, J=6.8 Hz, 2H), 3.56 (s, 3H), 3.28 (s, 3H),2.12 (s, 3H), 1.31-1.28 (m, 1H), 0.56-0.52 (m, 4H).

LCMS: 455 (M+H⁺).

Example 93N-[1-(cyclopropylmethyl)-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide

The title compound of Example 92, step 1 (100 mg, 0.24 mmol), 3-methoxy1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(78 mg, 0.29 mmol), K₂CO₃ (100 mg, 0.72 mmol) and Pd(dppf)Cl₂ (18 mg,0.024 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ were heated at 85° C.for 3 hr. After cooling to RT, the mixture was filtered, rinsing withEtOAC. The combined filtrate/rinse was diluted with water. Afterextraction with EtOAc (50 mL×3), the combined extracts were dried overNa₂SO₄, filtered, concentrated, and the residue was washed with ether(20 mL) to give the title compound (59 mg, 52%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.82 (s, 1H), 7.73 (d, J=2.4 Hz,1H), 7.43 (s, 1H), 7.17 (d, J=2.0 Hz, 1H), 4.37 (d, J=6.8 Hz, 2H), 3.84(s, 3H), 3.56 (s, 3H), 3.28 (s, 3H), 1.36-1.34 (m, 1H), 0.59-0.51 (m,4H). LCMS: 471 (M+H⁺).

Example 94N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamidehydrochloride Step 1: 5-bromo-N-butyl-3-fluoro-2-nitroaniline

5-bromo-1,3-difluoro-2-nitrobenzene (2.50 g, 10.5 mmol), K₂CO₃ (4.40 g,31.5 mmol) and n-butylamine (768 mg, 10.5 mmol) in THF (70 mL) werestirred at RT overnight. Water (100 mL) was added, and the mixture wasextracted with DCM (50 mL×2). The combined extracts were washed withbrine, dried over Na₂SO₄, concentrated, and the residue was purified bysilica gel chromatography (PE/EtOAc=100:1) to give the title compound(1.5 g, 50%) as a yellow solid. LCMS: 291, 293 (M+H⁺).

Step 2: N-[5-bromo-3-(butylamino)-2-nitrophenyl]methanesulfonamide

To MeSO₂NH₂ (563 mg, 5.93 mmol) in DMF (25 mL) was added t-BuOK (466 mg,4.16 mmol) at RT. The mixture was stirred for 30 min, and the titlecompound of step 1 (860 mg, 2.97 mmol) was then added and stirringcontinued overnight. The mixture was poured into ice water (50 mL), andthe pH was adjusted to 6-7 with HOAc. The resulting mixture wasextracted with EtOAc (30 mL×2). The combined extracts were washed withbrine, dried over Na₂SO₄, and concentrated to give a residue which waswashed with ether (20 mL) to give the title compound (450 mg, 41%) as ared solid. ¹H NMR (400 MHz, CDCl₃): δ 10.33 (s, 1H), 8.37 (s, 1H), 7.13(d, J=1.6 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 3.29-3.24 (m, 2H), 3.14 (s,3H), 1.76-1.69 (m, 2H), 1.53-1.45 (m, 2H), 0.99 (t, J=7.6 Hz, 3H). LCMS:366, 368 (M+H⁺).

Step 3: N-[2-amino-5-bromo-3-(butylamino)phenyl]methanesulfonamide

The title compound of step 2 (450 mg, 1.23 mmol) was suspended in MeOH(30 mL). Saturated aqueous NH₄Cl (10 mL) and Fe (345 mg, 6.16 mmol) wereadded, and the mixture was heated at 85° C. for 1 hr and then filtered.The insoluble components were rinsed with methanol (30 mL), and thecombined filtrate/rinse was diluted with water and extracted with EtOAc(40 mL×2). The combined extracts were dried over Na₂SO₄, filtered, andconcentrated to give the the title compound (400 mg, 97%) as a whitesolid. LCMS: 336, 338 (M+H⁺).

Step 4: N-(6-bromo-1-butyl-2-methylbenzimidazol-4-yl)methanesulfonamide

To the title compound of step 3 (300 mg, 0.9 mmol) in 4 M HCl (0.5 mL,2.0 mmol) was added 2,4-pentanedione (448 mg, 4.5 mmol). The mixture washeated at 75° C. for 1 hr and then cooled to RT, diluted with water,neutralized with aqueous, saturated NaHCO₃, and extracted with EtOAc (30mL×2). The combined extracts were washed with brine, dried over Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(PE:EtOAc=1:1) to give the title compound (230 mg, 72%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.60 (d, J=1.8 Hz, 1H), 7.18 (d,J=1.8 Hz, 1H), 4.16 (t, J=7.5 Hz, 2H), 3.20 (s, 3H), 2.54 (s, 3H),1.63-1.68 (m, 2H), 1.34-1.26 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). LCMS: 360,362 (M+H⁺).

Step 5:N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamide

The title compound of step 4 (100 mg, 0.28 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(83 mg, 0.33 mmol), K₂CO₃ (115 mg, 0.84 mmol) and Pd(dppf)Cl₂ (21 mg,0.028 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ were heated at 85° C.for 3 hr. After cooling to RT, the mixture was filtered, diluted withwater (20 mL), and extracted with EtOAc (30 mL×3). The combined extractswere dried over Na₂SO₄, filtered, concentrated, and the residue waspurified by prep-TLC (DCM:MeOH=20:1) to give the title compound (45 mg,40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 7.91(d, J=2.8 Hz, 1H), 7.73 (s, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.19 (d, J=1.2Hz, 1H), 4.23-4.19 (m, 2H), 3.54 (s, 3H), 3.19 (s, 3H), 2.57 (s, 3H),2.11 (s, 3H), 1.74-1.69 (m, 2H), 1.36-1.30 (m, 2H), 0.91 (t, J=7.2 Hz,3H). LCMS: 403 (M+H⁺).

Step 6:N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamidehydrochloride

The title compound of step 5 (45 mg, 0.11 mmol) in DCM (3 mL) wasconverted to the hydrochloride by adding 2M HCl in methanol (0.55 mL, 11mmol) at ice bath temperature. After stirring 5 min, the mixture wasconcentrated under reduced pressure. DCM (3 mL) was added and evaporatedtwice. The resulting residue was dried under vacuum to give the titlecompound (39 mg, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.09 (s, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=2.4 Hz,1H), 7.58 (s, 1H), 4.44-4.41 (m, 2H), 3.57 (s, 3H), 3.16 (s, 3H), 2.86(s, 3H), 2.13 (s, 3H), 1.83-1.79 (m, 2H), 1.43-1.37 (m, 2H), 0.93 (t,J=7.2 Hz, 3H).

LCMS: 403 (M+H⁺).

Example 95N-[1-butyl-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamidehydrochloride Step 1:N-[1-butyl-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methyl-benzimidazol-4-yl]methanesulfonamide

The title compound of Example 94, step 4 (100 mg, 0.28 mmol),3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(89 mg, 0.33 mmol), K₂CO₃ (116 mg, 0.84 mmol) and Pd(dppf)Cl₂ (21 mg,0.028 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ were heated at 85° C.for 3 hr. After cooling to RT, the mixture was filtered, diluted withwater (20 mL), and extracted with EtOAc (50 mL×3). The combined extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waswashed with EtOAc (5 mL) and then dried under vacuum to give the titlecompound (90 mg, 78%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ9.60 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H),4.25-4.20 (m, 2H), 3.82 (s, 3H), 3.54 (s, 3H), 3.21 (s, 3H), 2.57 (s,3H), 1.75-1.70 (m, 2H), 1.34-1.29 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). LCMS:419 (M+H⁺).

Step 2:N-[1-butyl-6-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4-yl]methanesulfonamidehydrochloride

The title compound of step 1(90 mg, 0.22 mmol) in DCM (3 mL) wasconverted to the hydrochloride by adding 2M HCl in methanol (1.1 mL, 22mmol) at ice bath temperature. After stirring 5 min, the mixture wasconcentrated under reduced pressure. DCM (3 mL) was added and evaporatedtwice. The resulting residue was dried under vacuum to give the titlecompound (88 mg, 90%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ10.02 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.57 (s, 1H), 7.19(d, J=2.1 Hz, 1H), 4.45-4.41 (m, 2H), 3.84 (s, 3H), 3.56 (s, 3H), 3.16(s, 3H), 2.85 (s, 3H), 1.83-1.77 (m, 2H), 1.39-1.34 (m, 2H), 0.93 (t,J=7.2 Hz, 3H).

LCMS: 419 (M+H⁺).

Example 96 5-[3-(cyclopropylmethyl)-2-methyl-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-one Step 1:4-bromo-2-(methylsulfanylmethyl)-6-nitroaniline

To a solution of 4-bromo-2-nitroaniline (5.0 g, 23 mmol) and dimethylsulfide (8.4 mL, 115 mmol) in DCM (150 mL) was added NCS (15.4 g, 115mmol). The resulting mixture was stirred for 30 min at RT. Triethylamine(16 ml, 115 mmol) was added and the mixture was heated to reflux for 15hr. The reaction was cooled to RT, diluted with 10% NaOH aqueoussolution (30 mL) and extracted with DCM (50 mL×3). The combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE:EtOAc=20:1 to 10:1) to give the titlecompound (1.5 g, 24%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.28(d, J=2.4 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 6.68-6.66 (br, 2H), 3.73 (s,2H), 2.04 (s, 3H).

Step 2: 5-bromo-3-(methylsulfanylmethyl)benzene-1,2-diamine

The title compound was prepared in a manner similar to Example 32, step2, by substituting the title compound from step 1 for6-bromo-1-[(3-fluorophenyl)methyl]-4-nitrobenzimidazole. ¹H NMR (300MHz, CDCl₃): δ 6.81 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 3.62 (s,2H), 2.00 (s, 3H).

Step 3: 6-bromo-2-methyl-4-(methylsulfanylmethyl)-1H-benzimidazole

A mixture of the title compound from step 2 (300 mg, 1.2 mmol) andpentane-2,4-dione (0.25 mL, 2.4 mmol) in ethanol (5 mL) and HCl (5 M,0.6 mL, 3 mmol) was heated at 80° C. for 1 hr. It was then was cooled toRT, neutralized with saturated NaHCO₃ solution (50 mL) and extractedwith EtOAc (30 mL×2). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound (310 mg, 94%) as a white solid. ¹HNMR (300 MHz, CDCl₃): δ 7.62 (s, 1H), 7.20 (s, 1H), 3.95 (s, 2H), 2.63(s, 3H), 1.99 (s, 3H).

Step 4:6-bromo-1-(cyclopropylmethyl)-2-methyl-4-(methylsulfanylmethyl)benzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting the title compound from step 3 for6-bromo-4-nitro-1H-benzimidazole and bromomethylcyclopropane forbromomethylbenzene. ¹H NMR (400 MHz, CDCl₃): δ 7.36 (s, 1H), 7.29 (s,1H), 4.06 (s, 2H), 3.95 (d, J=6.8 Hz, 2H), 2.62 (s, 3H), 2.09 (s, 3H),1.20-1.18 (m, 1H), 0.65-0.60 (m, 2H), 0.40-0.36 (m, 2H).

Step 5:6-bromo-1-(cyclopropylmethyl)-2-methyl-4-(methylsulfonylmethyl)benzimidazole

A mixture of the title compound from step 4 (150 mg, 0.46 mmol) andoxone (569 mg, 0.93 mmol) in DMF (8 ml) was stirred for 4 hr at RT. Itwas then poured over water (20 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound (145 mg, 88%) as a solid that was used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.49 (m, 2H),4.67 (s, 2H), 3.97 (d, J=6.6 Hz, 2H), 2.83 (s, 3H), 2.61 (s, 3H),1.22-1.18 (m, 1H), 0.69-0.62 (m, 2H), 0.42-0.38 (m, 2H). LCMS: 357; 359(M+H)⁺.

Step 6: 5-[3-(cyclopropylmethyl)-2-methyl-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 31, step6, by substituting the title compound from step 5 forN-(1-benzyl-6-bromobenzimidazol-4-yl)methanesulfonamide. ¹H NMR (300MHz, CDCl₃): δ 7.53 (s, 1H), 7.42 (m, 2H), 7.32 (s, 1H), 4.76 (s, 2H),4.05 (d, J=6.9 Hz, 2H), 3.64 (s, 3H), 2.85 (s, 3H), 2.65 (s, 3H), 2.24(s, 3H), 1.25-1.20 (m, 1H), 0.68-0.65 (m, 2H), 0.44-0.41 (m, 2H). LCMS:400 (M+H)⁺.

Example 975-[3-(cyclopropylmethyl)-2-ethoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-oneStep 1: 6-bromo-2-ethoxy-4-methyl-1H-benzimidazole

The title compound was prepared in a manner similar to Example 72, step4, by substituting 5-bromo-3-methylbenzene-1,2-diamine forN-[2-amino-5-bromo-3-(cyclopropyl-methylamino)phenyl]methanesulfonamide.

Step 2: 6-bromo-1-(cyclopropylmethyl)-2-ethoxy-4-methylbenzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting the title compound from step 1 for6-bromo-4-nitro-1H-benzimidazole and bromomethylcyclopropane forbromomethylbenzene. ¹H NMR (400 MHz, CDCl₃): δ 7.16 (s, 1H), 7.09 (s,1H), 4.61 (q, J=7.2 Hz, 2H), 3.78 (d, J=6.8 Hz, 2H), 2.52 (s, 3H), 1.46(t, J=7.2 Hz, 3H), 1.21-1.18 (m, 1H), 0.56-0.51 (m, 2H), 0.38-0.34 (m,2H).

Step 3:6-bromo-4-(bromomethyl)-1-(cyclopropylmethyl)-2-ethoxybenzimidazole

To a solution of the title compound from step 2 (200 mg, 0.65 mmol) andNBS (116 mg, 0.65 mmol) in dry benzene (4 mL) was added BPO (15.7 mg,0.06 mmol). The mixture was heated to reflux for 3 hr under N₂. Cooledto RT, it was partitioned between water (10 mL) and EtOAc (30 mL×3). Thecombined organic layers were washed with brine (35 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (PE/EtOAc=30:1) togive the title compound (90 mg, 35%). ¹H NMR (300 MHz, CDCl₃): δ7.34-7.25 (m, 2H), 4.82 (s, 2H), 4.63 (q, J=6.6 Hz, 2H), 3.78 (d, J=6.9Hz, 2H), 1.47 (t, J=6.9 Hz, 3H), 1.21-1.17 (m, 1H), 0.57-0.55 (m, 2H),0.38-0.36 (m, 2H).

Step 4:6-bromo-1-(cyclopropylmethyl)-2-ethoxy-4-(methylsulfonylmethyl)benzimidazole

A mixture of the title compound from step 3 (175 mg, 0.45 mmol) andNaSO₂Me (138 mg, 1.4 mmol) in DMF (10 mL) was heated at 65° C. for 2 hr.The reaction mixture was cooled to RT and partitioned between water (10mL) and DCM (20 mL×2). The combined organic layers were washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was suspended in PE/EtOAc (10 mL, 10:1)and filtered. The cake was dried to give the title compound (170 mg,97%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, J=1.8 Hz, 1H), 7.33(d, J=1.8 Hz, 1H), 4.61-4.54 (m, 4H), 3.78 (d, J=7.2 Hz, 2H), 2.80 (s,3H), 1.47 (t, J=7.2 Hz, 3H), 1.22-1.17 (m, 1H), 0.60-0.55 (m, 2H),0.40-0.36 (m, 2H).

LCMS: 387; 389 (M+H)⁺.

Step 5: 5-[3-(cyclopropylmethyl)-2-ethoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 31, step6, by substituting6-bromo-1-(cyclopropylmethyl)-2-ethoxy-4-(methylsulfonylmethyl)benzimidazole forN-(1-benzyl-6-bromobenzimidazol-4-yl)methanesulfonamide. ¹H NMR (400MHz, DMSO-d₆): δ 7.93 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.35 (s, 1H),4.65 (s, 2H), 4.58 (q, J=7.2 Hz, 2H), 3.93 (d, J=7.2 Hz, 2H), 3.54 (s,3H), 2.96 (s, 3H), 2.10 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.29-1.26 (m,1H), 0.51-0.49 (m, 2H), 0.42-0.40 (m, 2H). LCMS: 430 (M+H)⁺.

Example 985-[3-(cyclopropylmethyl)-2-ethoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 97 bysubstituting3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 5. ¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, 1H), 7.19 (s, 1H), 7.12(s, 1H), 6.90 (s, 1H), 4.67 (s, 2H), 4.64-4.59 (m, 2H), 3.91-3.87 (m,5H), 3.65 (s, 3H), 2.83 (s, 3H) 1.49-1.46 (m, 3H), 1.25-1.24 (m, 1H),0.60-0.57 (m, 2H), 0.43-0.41 (m, 2H). LCMS: 446 (M+H)⁺.

Example 995-[3-(cyclopropylmethyl)-2-methoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-oneStep 1: 6-bromo-2-methoxy-4-(methylsulfanylmethyl)-1H-benzimidazole

The title compound was prepared in a manner similar to Example 73, step1, by substituting the title compound from Example 96, step 2, forN-[2-amino-5-bromo-3-(cyclopropylmethylamino)phenyl]methanesulfonamide.LCMS: 287; 289 (M+H)⁺.

Step 2:6-bromo-1-(cyclopropylmethyl)-2-methoxy-4-(methylsulfanylmethyl)benzimidazole

The title compound was prepared in a manner similar to Example 31, step3, by substituting the title compound from step 1 for6-bromo-4-nitro-1H-benzimidazole and bromomethylcyclopropane forbromomethylbenzene. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.21 (m, 2H), 4.17(s, 3H), 3.99 (s, 2H), 3.78 (d, J=6.8 Hz, 2H), 2.10 (s, 3H), 1.22-1.17(m, 1H), 0.57-0.52 (m, 2H), 0.38-0.33 (m, 2H). LCMS: 341; 343 (M+H)⁺.

Step 3:6-bromo-1-(cyclopropylmethyl)-2-methoxy-4-(methylsulfonylmethyl)benzimidazole

The title compound was prepared in a manner similar to Example 96, step5, by substituting the title compound from step 2 for6-bromo-1-(cyclopropylmethyl)-2-methyl-4-(methylsulfanylmethyl)benzimidazole.LCMS: 373; 375 (M+H)⁺.

Step 4: 5-[3-(cyclopropylmethyl)-2-methoxy-7-(methylsulfonylmethyl)benzimidazol-5-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 31, step6, by substituting the title compound from step 3 forN-(1-benzyl-6-bromobenzimidazol-4-yl)methanesulfonamide. ¹H NMR (300MHz, CD₃OD): δ 7.85-7.82 (m, 2H), 7.54 (s, 1H), 7.39 (s, 1H), 4.77 (s,2H), 4.22 (s, 3H), 3.96 (q, J=6.9 Hz, 2H), 3.66 (s, 3H), 2.90 (s, 3H),2.21 (s, 3H), 1.32-1.26 (m, 1H), 0.56-0.54 (m, 2H), 0.44-0.42 (m, 2H).LCMS: 416 (M+H)⁺.

Example 1005-[2-cyclopropyl-5-(ethylsulfonylmethyl)-1,3-benzoxazol-7-yl]-3-methoxy-1-methylpyridin-2-one

The title compound (44 mg) was prepared as an off-white solid in asimilar manner to Example 56 except that sodium ethanesulfinate wassubstituted for sodium methanesulfinate in step 5 and3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewas substituted for1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein step 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.24 (m, 7H) 2.33-2.36(m, 1H) 3.02-3.07 (m, 2H) 3.57 (s, 3H) 3.82 (s, 3H) 4.54-4.58 (s, 2H)7.27-7.29 (m, 1H) 7.55-7.57 (m, 2H) 7.85-7.86 (m, 1H). LCMS (M+H)⁺=403.

Example 101N-[3-(cyclopropylmethyl)-5-(1,5-dimethyl-6-oxopyridin-3-yl)-2-oxo-1,3-benzoxazol-7-yl]methanesulfonamide Step 1:5-bromo-3-(cyclopropylmethyl)-7-nitro-1,3-benzoxazol-2-one

A mixture of 5-bromo-7-nitro-3H-1,3-benzoxazol-2-one (700 mg, 2.69mmol), K₂CO₃ (1.1 g, 8.07 mmol) and bromomethylcyclopropane (727 mg,5.38 mmol) in DMF (30 mL) was stirred at 80° C. for 4 hr. The reactionwas cooled to RT, diluted with ice water (50 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography on silica gel (PE:EtOAc=20:1) to give the titlecompound (480 mg, 57%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ8.03 (d, J=1.8 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 3.75 (d, J=7.5 Hz, 2H),1.26-1.19 (m, 1H), 0.70-0.64 (m, 2H), 0.50-0.45 (m, 2H).

Step 2: 7-amino-5-bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2-one

A mixture of the title compound from step 1 (550 mg, 1.76 mmol) and Fe(493 mg, 8.81 mmol) in a methanol/saturated NH₄Cl aqueous solution (30mL/10 mL) was stirred at 85° C. for 1 hr. The reaction mixture wasfiltered and the cake was washed with methanol (10 mL×2). The filtratewas diluted with water (50 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (30 mL×3), dried overNa₂SO₄, filtered and concentrated. The residue was washed with ether (10mL×2) to give the title compound (450 mg, 91%) as a yellow solid. LCMS:300, 302 (M+NH₄)⁺.

Step 3:N-[5-bromo-3-(cyclopropylmethyl)-2-oxo-1,3-benz-oxazol-7-yl]methanesulfonamide

To a solution of the title compound from step 2 (250 mg, 0.89 mmol) inDCM (10 mL) at 0° C. was added TEA (895 mg, 8.86 mmol) and MsCl (505 mg,4.43 mmol). The reaction was allowed to warm to RT and stirred for 2 hr.It was then poured over ice-water and extracted with DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in THF (5 mL) and TBAF (2 mL, 1Min THF) was added. The reaction was stirred at RT for 1 hr. Water (30mL) was added and the resulting precipitate was filtered. The solidswere washed with water (10 mL×2) and ether (5 mL), and dried underreduced pressure to give the title compound (200 mg, 69%) as a solid. ¹HNMR (300 MHz, CDCl₃): δ 7.45 (d, J=1.5 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H),6.66 (s, 1H), 3.68 (d, J=7.5 Hz, 2H), 3.15 (s, 3H), 1.22-1.20 (m, 1H),0.68-0.63 (m, 2H), 0.48-0.43 (m, 2H).

Step 4:N-[3-(cyclopropylmethyl)-5-(1,5-dimethyl-6-oxopyridin-3-yl)-2-oxo-1,3-benzoxazol-7-yl]methanesulfonamide

A mixture of the title compound from step 3 (100 mg, 0.28 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(83 mg, 0.33 mmol), K₂CO₃ (116 mg, 0.84 mmol) and Pd(dppf)Cl₂ (21 mg,0.028 mmol) in dioxane/H₂O (9 mL/3 mL) under N₂ was heated to 85° C. for3 hr. The reaction mixture was cooled to RT and filtered. The filtratewas diluted with water and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by preparative TLC (EtOAc) to give the titlecompound (42 mg, 38%) as a solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.94 (s,1H), 8.97 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.17 (s, 1H), 3.75 (d,J=6.9 Hz, 2H), 3.53 (s, 3H), 3.14 (s, 3H), 2.10 (s, 3H), 1.34-1.31 (m,1H), 0.54-0.45 (m, 4H). LCMS: 404 (M+H).

Example 102N-[5-(1,5-dimethyl-6-oxopyridin-3-yl)-3-[(4-fluorophenyl)methyl]-2-oxo-1,3-benzoxazol-7-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 101 bysubstituting 1-(bromomethyl)-4-fluoro-benzene forbromomethylcyclopropane in step 1. ¹H NMR (300 MHz, DMSO-d₆): δ 9.95 (s,1H), 7.91 (d, J=1.8 Hz, 1H), 7.66 (s, 1H), 7.52-7.43 (m, 3H), 7.24-7.17(m, 3H), 5.07 (s, 2H), 3.52 (s, 3H), 3.13 (s, 3H), 2.09 (s, 3H). LCMS:458 [M+H]⁺.

Example 103N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 72 bysubstituting ethanesulfonamide for methanesulfonamide in step 2 andtetramethylorthocarbonate for tetraethylorthocarbonate in step 4. ¹H NMR(300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.49 (s,1H), 7.15 (s, 1H), 4.14 (s, 3H), 3.92 (m, 2H), 3.52 (s, 3H), 3.30 (m,2H), 2.10 (s, 3H), 1.37 (dd, J=7.2 Hz, 3H), 1.27 (m, 1H), 0.48 (m, 2H),0.40 (m, 2H). LCMS: 431.2 (M+H)+.

Example 104N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4-yl]methanesulfonamide

The title compound was prepared in a manner similar to Example 64 bysubstituting benzyl bromide for 1-(bromomethyl)-4-fluoro-benzene in step2. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H),7.80 (s, 1H), 7.30 (m, 5H), 7.20 (s, 1H), 5.55 (s, 2H), 3.55 (s, 3H),3.10 (s, 3H), 2.11 (s, 3H). LCMS: 441.1 (M+H)⁺.

Example 105N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4-fluorophenyl)methyl]indazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 64 bysubstituting ethanesulfonyl chloride for methanesulfonyl chloride instep 5. ¹H NMR (300 MHz, CDCl3-d₆) δ 7.44 (s, 1H), 7.41 (s, 1H), 7.32(s, 1H), 7.21 (m, 1H), 7.0 (m, 3H), 6.82 (s, 1H), 5.38 (s, 2H), 3.64 (s,3H), 3.24 (q, J=7.4 Hz, 2H), 2.24 (s, 3H), 1.42 (q, J=7.4 Hz, 3H).

LCMS: 473.1 (M+H)⁺.

Example 106N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoroindazol-4-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 64 bysubstituting benzyl bromide for 1-(bromomethyl)-4-fluoro-benzene in step2 and ethanesulfonyl chloride for methanesulfonyl chloride in step 5. ¹HNMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.86 (s,1H), 7.79 (s, 1H), 7.31 (m, 5H), 7.18 (s, 1H), 5.54 (s, 2H), 2.05 (q,J=7.4 Hz, 2H), 2.11 (s, 3H), 1.27 (t, J=7.4 Hz, 3H). LCMS: 455.1 (M+H)⁺.

II. Biological Evaluation Example 1 In Vitro Enzyme Inhibition Assay

Determination of the IC₅₀ for the heterocyclic derivative BRD4inhibitors disclosed herein was performed as follows. His-tagged BRD4was cloned, expressed and purified to homogeneity. Filipakopoulos etal., 468 Nature 1067 (2010). BRD4 binding and inhibition was assessed bymonitoring the interaction of biotinylated H4-tetraacetyl peptide(AnaSpec, H4K5/8/12/16 (Ac), biotin—labeled) with the target using theAlphaScreen technology (Life Technologies). In a 384-well ProxiPlateBRD4 (BD1) (2 nM final) was combined with peptide (15 nM final) in 50 mMHEPES (pH 7.3), 10 mM NaCl, 0.25 mM TCEP, 0.1% (w/v) BSA, and 0.005%(w/v) Brij-35 either in the presence of DMSO (final 0.4% DMSO) orcompound dilution series in DMSO. After 20 min incubation at RT, Alphastreptavidin donor beads and Nickel Chelate acceptor beads were added toa final concentration of 5 μg/mL. After 2 hr of equilibration, plateswere read on an Envision instrument and the IC₅₀ was calculated using afour parameter non-linear curve fit.

The ability of the compounds disclosed herein to inhibit BRD4 activitywas quantified and the respective IC₅₀ value was determined. The IC₅₀values of various compounds disclosed herein is provided in Table 3.

Example 2 In Vitro Cell-Based Assay

A colorimetric cellular proliferation assay (Cell-MTS assay) wasperformed to assess the ability of the heterocyclic derivative BRD4inhibitors disclosed herein to effect the proliferation of establishedcancer cell lines.

Assay Principle:

The Cell-MTS assay is a 7-day plate-based colorimetric assay whichquantifies the amount of newly generated NADH in the presence or absenceof test compound. The NADH level is used for the quantification ofcancer cell proliferation.

Assay Method:

Established cancer cell lines with a variety of driving mutations wereobtained from American Type Culture Collection (ATCC) and routinelypassaged according to ATCC protocols. For routine assay, these cellswere seeded at densities which enabled ˜90% confluence after 7 days ofculture. Raji, human Burkitts lymphoma cells, (cMYC) were seeded at15,000 cells per 96-well. HL-60, human proleukemia cells, (NRAS, p16,p53, c-Myc amplified) were seeded at 5,000 cells per 96-well. NCI-H460,human non-small cell lung cancer cells, (KRAS, PIK3CA, STLK11, p16) wereseeded at 3,000 cells per 96-well. 24 hr after plating, cells receivedan 11 point dilution of test compound with final concentration rangesfrom 100 □M to 2.0 nM. Cells were incubated in the presence of compoundfor 168 hr at 37° C., and 5% CO2. At the end of this incubation period,80 □L of media is removed and 20 □L of CellTiter 96® AQueousNon-Radioactive Cell Proliferation Assay solution (Promega) was added.The cells were incubated until the OD490 was >0.6. IC50 values werecalculated using the IDBS XLfit software package and include backgroundsubtracted OD490 values and normalization to DMSO controls. Cellularproliferation IC50 values were uploaded and archived using the ChemBiography Platform. Table 3 provides the results of the in vitro enzymeinhibition assay experiments and the in vitro cell-based assayexperiments performed with the compounds disclosed herein:

TABLE 3 Ex. BRD4 Raji HL-60 H460 No Coumpound Name IC₅₀* IC₅₀ IC₅₀ IC₅₀1 2-methyl-4-(2-methyl-1,1-dioxo-3H-1,2-benzothiazol- B B B B6-yl)isoquinolin-1-one 24-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-2- B C B Cmethylisoquinolin-1-one 3 5-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2- A C BC benzothiazol-6-yl)-1,3-dimethylpyridin-2-one 44-(5-methoxy-2-methyl-1,1-dioxo-3H-1,2- A B A Bbenzothiazol-6-yl)-2-methylisoquinolin-1-one 55-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H- A B A C1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one 64-[5-(cyclopropylmethoxy)-2-methyl-1,1-dioxo-3H- A B A B1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-one 74-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2- A A A Bbenzothiazol-6-yl]-2-methylisoquinolin-1-one 85-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2- A B A Bbenzothiazol-6-yl]-1,3-dimethylpyridin-2-one 91,3-dimethyl-5-[2-methyl-1,1-dioxo-5-(2,2,2- A B A Ctrifluoroethoxy)-3H-1,2-benzothiazol-6- yl]pyridine-2-one 102-methyl-4-[2-methyl-1,1-dioxo-5-(2,2,2- A B A Btrifluoroethoxy)-3H-1,2-benzothiazol-6- yl]isoquinolin-1-one 115-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H- A A A C1,2-benzothiazol-6-yl]-1,3-dimethylpyridin-2-one 125-[5-(2,4-difluorophenoxy)-2-methyl-1,1-dioxo-3H- A — — —1,2-benzothiazol-6-yl]-1-methylpyridin-2-one 134-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3- A A A Bdihydroindol-6-yl]-2-methylisoquinolin-1-one 144-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3- A A A Bdihydroindol-6-yl]-2-methylisoquinolin-1-one 155-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3- A A A Cdihydroindol-6-yl]-1,3-dimethylpyridin-2-one 165-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3- A A A Cdihydroindol-6-yl]-1,3-dimethylpyridin-2-one 17N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol- A A A B4-yl]methanesulfonamide 18N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indol- A A A B4-yl]methanesulfonamide 19N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3- A A A Bdihydroindol-4-yl]methanesulfonamide 20N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-2,3- A A A Bdihydroindol-4-yl]methanesulfonamide 215-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-1,3- A — — —dimethylpyridin-2-one 22 N-[2-(1,5-dimethyl-6-oxopyridin-3-yl)-9-[(4- A— — — fluorophenyl)methyl]-8-methylpurin-6- yl]methanesulfonamide 235-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7- A B A Cyl)-1,3-dimethylpyridin-2-one 244-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7- A A A Byl)-2-methylisoquinolin-1-one 251,3-dimethyl-5-(5-methylsulfonyl-2-phenyl-1- A — — —benzofuran-7-yl)pyridin-2-one 262-methyl-4-(5-methylsulfonyl-2-phenyl-1-benzofuran- A A A B7-yl)isoquinolin-1-one 27 N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3- AA A B yl)benzotriazol-4-yl]ethanesulfonamide 28N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4- A A A Bfluorophenyl)methyl]benzotriazol-4- yl]ethanesulfonamide 294-[6-(cyclopropylmethoxy)-1-methyl-3- A A A Bmethylsulfonylindazol-5-yl]-2- methylisoquinolin-1-one 304-[6-(cyclopropylmethoxy)-3-ethylsulfonyl- A A A B1-methylindazol-5-yl]-2-methylisoquinolin-1-one 31N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3- A A A Byl)benzimidazol-4-yl]methanesulfonamide 32N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3- A A A Bfluorophenyl)methyl]benzimidazol-4- yl]methanesulfonamide 33N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3- A A A Bfluorophenyl)methyl]benzimidazol-4- yl]ethanesulfonamide 34N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2- A A A Cmethylbenzimidazol-4-yl]methanesulfonamide 35N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3- A A A Bfluorophenyl)methyl]-2-methylbenzimidazol-4- yl]methanesulfonamide 36N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3- A A A Afluorophenyl)methyl]-2-methylbenzimidazol-4- yl]ethanesulfonamide 37N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4- A A A Bfluorophenyl)methyl]-2-methylbenzimidazol-4- yl]methanesulfonamide 38N-[1-[(4-fluorophenyl)methyl]-6-(5-methoxy-1- A A A Cmethyl-6-oxopyridin-3-yl)-2-methylbenzimidazol-4- yl]methanesulfonamide39 N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A A A Coxopyridin-3-yl)-2-methylbenzimidazol-4- yl]methanesulfonamide 40N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3- A A A Cyl)benzimidazol-4-yl]ethanesulfonamide 41N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6- A A A Boxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide 42N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3- A A A Byl)indazol-4-yl]ethanesulfonamide 43N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4- A A A Afluorophenyl)methyl]indazol-4-yl]ethanesulfonamide 44N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1- A A A Bphenylethyl)benzimidazol-4-yl]methanesulfonamide 45N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1- A A A Bphenylethyl)benzimidazol-4-yl]methanesulfonamide 46N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(2R)-1- A A A Cmethoxypropan-2-yl]-2-methylbenzimidazol-4- yl]methanesulfonamide 47N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A A A C1,3-benzoxazol-5-yl]ethanesulfonamide 48N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)- A A A A1,3-benzoxazol-5-yl]ethanesulfonamide 494-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3- A A A Bdihydro-1,4-benzoxazin-6-yl]-2- methylisoquinolin-1-one 505-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3- A A A Cdihydro-1,4-benzoxazin-6-yl]-1,3- dimethylpyridin-2-one 51N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A B A C1,3-benzoxazol-5-yl]propane-2-sulfonamide 52N-[2-cyclopentyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A A A C1,3-benzoxazol-5-yl]ethanesulfonamide 53N-[2-cyclopentyl-7-(2-methyl-1-oxoisoquinolin-4-yl)- A A A C1,3-benzoxazol-5-yl]ethanesulfonamide 54N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A — — —3-methylbenzimidazol-5-yl]ethanesulfonamide 55N-[2-cyclopropyl-3-methyl-7-(2-methyl-1- A — — —oxoisoquinolin-4-yl)benzimidazol-5- yl]ethanesulfonamide 565-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3- A B A Cbenzoxazol-7-yl]-1,3-dimethylpyridin-2-one 57N-[2-cyclopentyl-7-(5-methoxy-1-methyl-6- A A A Coxopyridin-3-yl)-1,3-benzoxazol-5- yl]ethanesulfonamide 585-[6-(cyclopropylmethoxy)-1-methyl-3- A A A Cmethylsulfonylindazol-5-yl]-1,3- dimethylpyridin-2-one 595-[6-(cyclopropylmethoxy)-1-methyl-3- A A A Cmethylsulfonylindazol-5-yl]-3-methoxy-1- methylpyridin-2-one 60N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4- A A A Cfluorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-4-yl]methanesulfonamide 61N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2- A A A Cmethylimidazo[4,5-c]pyridin-4- yl]methanesulfonamide 62N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6- A A A Coxopyridin-3-yl)-2-methylimidazo[4,5-c]pyridin-4- yl]methanesulfonamide63 5-[2-cyclopropyl-5-(methylsulfonylmethyl)-1,3- A — — —benzoxazol-7-yl]-3-methoxy-1-methylpyridin-2-one 64N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4- A A A Cfluorophenyl)methyl]indazol-4-yl]methanesulfonamide 65N-[3-fluoro-1-[(4-fluorophenyl)methyl]-6-(5-methoxy- A A A C1-methyl-6-oxopyridin-3-yl)indazol-4- yl]methanesulfonamide 66N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A A A Coxopyridin-3-yl)-3-fluoroindazol-4- yl]methanesulfonamide 675-(3-benzyl-2-methyl-7-methylsulfonylbenzimidazol- A A A C5-yl)-1,3-dimethylpyridin-2-one 685-(3-benzyl-7-ethylsulfonyl-2-methylbenzimidazol-5- A B B Cyl)-3-methoxy-1-methylpyridin-2-one 695-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2- A — — —methylbenzimidazol-5-yl]-1,3-dimethylpyridin-2-one 705-[3-(cyclopropylmethyl)-7-ethylsulfonyl-2- A — — —methylbenzimidazol-5-yl]-3-methoxy-1- methylpyridin-2-one 715-[3-(cyclopropylmethyl)-2-methyl-7- A C B Cmethylsulfonylbenzimidazol-5-yl]-1,3- dimethylpyridin-2-one 72N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A A A Boxopyridin-3-yl)-2-ethoxybenzimidazol-4- yl]methanesulfonamide 73N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A A A Boxopyridin-3-yl)-2-methoxybenzimidazol-4- yl]methanesulfonamide 74N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A — — —oxopyridin-3-yl)-2-ethylbenzimidazol-4- yl]methanesulfonamide 755-(1-ethyl-4-methylsulfonylindol-2-yl)-1,3- A — — —dimethylpyridin-2-one 765-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]- A — — —1,3-dimethylpyridin-2-one 775-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]- A — — —1,3-dimethylpyridin-2-one 784-[1-(cyclopropylmethyl)-4-methylsulfonylindol-2-yl]- A — — —2-methylisoquinolin-1-one 79N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)- A A A A1-benzofuran-5-yl]methanesulfonamide 80N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A A A B1-benzofuran-5-yl]methanesulfonamide 81N-[9-(cyclopropylmethyl)-2-(1,5-dimethyl-6- A — — —oxopyridin-3-yl)-8-methylpurin-6- yl]methanesulfonamide 82N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)- A A A A1-benzofuran-5-yl]ethanesulfonamide 83N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-phenyl-1- A B B Bbenzofuran-5-yl]methanesulfonamide 84N-[7-(2-methyl-1-oxoisoquinolin-4-yl)-2-phenyl-1- A A A Abenzofuran-5-yl]methanesulfonamide 858-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- A B A C6-methyl-2,3-dihydro-1H-indolizin-5-one 86N-[4-(2,4-difluorophenoxy)-3-(6-methyl-5-oxo-2,3- A A A Cdihydro-1H-indolizin-8- yl)phenyl]methanesulfonamide 878-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- A A A C2,2,6-trimethyl-1,3-dihydroindolizin-5-one 88N-[4-(2,4-difluorophenoxy)-3-(2,2,6-trimethyl-5-oxo- A A A C1,3-dihydroindolizin-8-yl)phenyl]methanesulfonamide 898-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- B — — —1,1-difluoro-6-methyl-2,3-dihydroindolizin-5-one 908-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- A — — —1-fluoro-6-methyl-2,3-dihydro-1H-indolizin-5-one 915-[1-(2-cyclopropylethyl)-4-methylsulfonylindol-2-yl]- A A A C3-methoxy-1-methylpyridin-2-one 92N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A A A Boxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide 93N-[1-(cyclopropylmethyl)-6-(5-methoxy-1-methyl-6- A A A Coxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide 94N-[1-butyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2- A A A Cmethylbenzimidazol-4-yl]methanesulfonamide 95N-[1-butyl-6-(5-methoxy-1-methyl-6-oxopyridin-3- A A A Cyl)-2-methylbenzimidazol-4-yl]methanesulfonamide 965-[3-(cyclopropylmethyl)-2-methyl-7- A A A C(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 975-[3-(cyclopropylmethyl)-2-ethoxy-7- A A A C(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 985-[3-(cyclopropylmethyl)-2-ethoxy-7- A A A C(methylsulfonylmethyl)benzimidazol-5-yl]-3-methoxy-1-methylpyridin-2-one 99 5-[3-(cyclopropylmethyl)-2-methoxy-7- A A A C(methylsulfonylmethyl)benzimidazol-5-yl]-1,3- dimethylpyridin-2-one 1005-[2-cyclopropyl-5-(ethylsulfonylmethyl)-1,3- A A A Cbenzoxazol-7-yl]-3-methoxy-1-methylpyridin-2-one 101N-[3-(cyclopropylmethyl)-5-(1,5-dimethyl-6- A B B Coxopyridin-3-yl)-2-oxo-1,3-benzoxazol-7- yl]methanesulfonamide 102N-[5-(1,5-dimethyl-6-oxopyridin-3-yl)-3-[(4- A A A Cfluorophenyl)methyl]-2-oxo-1,3-benzoxazol-7- yl]methanesulfonamide 103N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6- A — — —oxopyridin-3-yl)-2-methoxybenzimidazol-4- yl]ethanesulfonamide 104N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3- A — — —fluoroindazol-4-yl]methanesulfonamide 105N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-3-fluoro-1-[(4- A — — —fluorophenyl)methyl]indazol-4-yl]ethanesulfonamide 106N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-3- A — — —fluoroindazol-4-yl]ethanesulfonamide4-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-2- A A A Bmethylisoquinolin-1-oneN-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)- A A A B1-benzofuran-5-yl]ethanesulfonamide *All IC₅₀ data were calculated μM.IC₅₀ data are designated within the following ranges: A: ≦0.5 μM;B: >0.5 μM to ≦5.0 μM; C: >5.0 μM

Example 3 In Vivo Xenograph Study—Antitumor Efficacy in Xenograft Modelsof NUT Midline Carcinoma (NMC)

Xenograft models of NMC in mice are used in this study. Matched cohortsof mice with established tumors are randomized to treatment with a testcompound or vehicle, administered by daily intraperitoneal injection.Before randomization and after four days of therapy, mice are evaluatedby 18F-fluorodeoxyglucose (FDG)-PET imaging. Tumor-volume measurementsare also made, as are measures of toxicity or weight loss. Tumors areobtained and sectioned and immunohistochemically examined for theBRD4-NUT oncoprotein, cell spreading, keratin expression, nuclear Ki67,and TUNEL staining. Paired samples from treated and untreated mice areprepared and analyzed using standardized protocols and commerciallyavailable software (i.e., ImageScopt; Aperio Technologies).

Example 4 In Vivo Xenograph Study—Antitumor Efficacy in Xenograft Modelsof MCF-7 Breast Cancer

Time release pellets containing 0.72 mg 17-β Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 37° C. in 5% CO₂. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width 2/2) is monitored biweekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with a test compound or vehicle daily for fourweeks. Tumor volume and body weight are monitored biweekly throughoutthe study. At the conclusion of the treatment period, plasma and tumorsamples are taken for pharmacokinetic and pharmacodynamic analyses,respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1 Oral Tablet

A tablet is prepared by mixing 48% by weight of a compound of Formula I,or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound of Formula I, or a pharmaceutically acceptablesalt thereof,

wherein, Ring A is an optionally substituted 5- or 6-membered heteroarylring containing at least one S or N atom, or an optionally substituted5- or 6-membered heterocyclyl ring containing at least one S or N atom;X2 is N or C—R¹², in which R¹² is hydrogen, halogen, alkyl, or alkoxy;X5 is N or C—R¹⁵, in which R¹⁵ is hydrogen, halogen, —CN, alkyl oralkoxy; X6 is N or C—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X,wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and G is:

wherein, R²² is alkyl; R²³ is hydrogen, halogen, or alkyl; oroptionally, when R²³ is alkyl, R²² and R²³ join to form an optionallysubstituted ring; R²⁵ is hydrogen, halogen, alkyl, alkoxy, or alkenyl;R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or alkenyl; oroptionally, when R²³ is hydrogen, R²⁵ is not hydrogen and R²⁶ is nothydrogen or halogen, R²⁵ and R²⁶ join to form an optionally substitutedring; provided that the compound of Formula I is not:4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-methylisoquinolin-1(2H)-one;2-methyl-4-(2-oxoindolin-6-yl)isoquinolin-1(2H)-one;4-methyl-6-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one; nor4-(1′-cyclobutyl-4H-spiro[benzo[d][1,3]dioxine-2,4′-piperidine]-6-yl)-2-methylisoquinolin-1(2H)-one.2. A compound of Formula II, or a pharmaceutically acceptable saltthereof,

wherein, Ring B is an optionally substituted 5- or 6-membered heteroarylring containing at least one S or N atom, or an optionally substituted5- or 6-membered heterocyclyl ring containing at least one S or N atom;X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or alkoxy; X3is N or C—R¹³, wherein R¹³ is —Y—Z, in which Y is a bond, —CH₂—, or—CH(C₁-C₄ alkyl)-; Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,—N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),—N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂,or —N(R^(a))SO₃R^(b); each R^(a) is independently selected fromhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; andR^(b) is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; X6 is N or C—R¹⁶, wherein R¹⁶ is hydrogen, halogen, or—W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and Gis described by:

wherein, R²² is alkyl; R²³ is hydrogen, halogen, or alkyl; or,optionally, when R²³ is alkyl, then R²² and R²³ join to form anoptionally substituted ring; R²⁵ is hydrogen, halogen, alkyl, alkoxy, oralkenyl; R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, oralkenyl; or, optionally, when R²³ is hydrogen, R²⁵ is not hydrogen andR²⁶ is not hydrogen or halogen, then R²⁵ and R²⁶ join to form anoptionally substituted ring.
 3. A compound of Formula III, or apharmaceutically acceptable salt thereof,

wherein, Ring C is an optionally substituted 5- or 6-membered heteroarylring containing at least one O, S or N atom; X2 is N or C—R¹², whereinR¹² is hydrogen, halogen, alkyl, or alkoxy; X3 is N or C—R¹³, whereinR¹³ is —Y—Z, in which Y is a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-; Z is—SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,—CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),—OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b); each R^(a) isindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen,—CN, alkyl, cycloalkyl, or alkoxy; and G is described by:

wherein, R²² is alkyl; R²³ is hydrogen, halogen, or alkyl; or,optionally, when R²³ is alkyl, then R²² and R²³ join to form anoptionally substituted ring; R²⁵ is hydrogen, halogen, alkyl, alkoxy, oralkenyl; R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, oralkenyl; or, optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, andR²⁶ is not hydrogen or halogen, then R²⁵ and R²⁶ join to form anoptionally substituted ring; provided that the compound of Formula IIIis neither4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one,nor4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.4. A compound of Formula IV, or a pharmaceutically acceptable saltthereof,

wherein, each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;R¹³ is —Y—Z, wherein Y is selected from a bond, —CH₂—, or —CH(C₁-C₄alkyl)-; Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂,—N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),—N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂,or —N(R^(a))SO₃R^(b); each R^(a) is independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R^(b) is alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R¹⁶ is alkyl,alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and Gis:

wherein, R²² is alkyl; R²³ is hydrogen, halogen, or alkyl; oroptionally, when R²³ is alkyl, then R²² and R²³ join to form anoptionally substituted ring; R²⁵ is hydrogen, halogen, alkyl, alkoxy, oralkenyl; R²⁶ is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, oralkenyl; or, optionally, when R²³ is hydrogen, R²⁵ is not hydrogen, andR²⁶ is not hydrogen or halogen, then R²⁵ and R²⁶ join to form anoptionally substituted ring.
 5. The compound of any one of claims 1-4,or a pharmaceutically acceptable salt thereof, wherein G is:


6. The compound of any one of claims 1-4, or a pharmaceuticallyacceptable salt thereof, wherein G is:


7. The compound of any one of claims 1-4, or a pharmaceuticallyacceptable salt thereof, wherein G is:


8. The compound of any one of claims 1-4, or a pharmaceuticallyacceptable salt thereof, wherein G is:


9. The compound of any one of claims 1-3, or a pharmaceuticallyacceptable salt thereof, wherein X2 is N.
 10. The compound of any one ofclaims 2 or 3, or a pharmaceutically acceptable salt thereof, wherein X3is N.
 11. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein X4 is N.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X5 is N.
 13. Thecompound of any one of claims 1 or 2, or a pharmaceutically acceptablesalt thereof, wherein X6 is N.
 14. The compound of any one of claims1-3, or a pharmaceutically acceptable salt thereof, wherein X2 is C—R¹².15. The compound of any one of claims 2 or 3, or a pharmaceuticallyacceptable salt thereof, wherein X3 is C—R¹³.
 16. The compound of claim3, or a pharmaceutically acceptable salt thereof, wherein X4 is C—R¹⁴.17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein X5 is C—R¹⁵.
 18. The compound of any one of claims 1 or2, or a pharmaceutically acceptable salt thereof, wherein X6 is C—R¹⁶.19. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein ring A is an optionally substituted 5- or 6-memberedheteroaryl ring containing at least one S or N atom.
 20. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein ring Ais an optionally substituted 5- or 6-membered heterocyclyl ringcontaining at least one S or N atom.
 21. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S or N atom.
 22. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein ring B is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one S or N atom.
 23. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein ring C is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one O, S or N atom.
 24. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein ring C is anoptionally substituted 5- or 6-membered heterocyclyl ring containing atleast one S or N atom.
 25. The compound of claim 19, 21 or 23, or apharmaceutically acceptable salt thereof, wherein the optionallysubstituted 5- or 6-membered heteroaryl ring contains at least one Satom.
 26. The compound of claim 19, 21 or 23, or a pharmaceuticallyacceptable salt thereof, wherein the optionally substituted 5- or6-membered heteroaryl ring contains at least one N atom.
 27. Thecompound of claim 20, 22, or 24, or a pharmaceutically acceptable saltthereof, wherein the optionally substituted 5- or 6-memberedheterocyclyl ring contains at least one S atom.
 28. The compound ofclaim 20, 22, or 24, or a pharmaceutically acceptable salt thereof,wherein the optionally substituted 5- or 6-membered heterocyclyl ringcontains at least one N atom.
 29. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X2 is C—R¹², X5 isC—R¹⁵, and X6 is C—R¹⁶, each as defined therein.
 30. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein X2 isC—R¹², X3 is C—R¹³, and X⁶ is C—R¹⁶, each as defined therein.
 31. Thecompound of claim 3, or a pharmaceutically acceptable salt thereof,wherein X2 is C—R¹², X3 is C—R¹³, and X4 is C—R¹⁴, each as definedtherein.
 32. The compound of claim 29, or a pharmaceutically acceptablesalt thereof, wherein ring A is illustrated by a formula selected fromthe group:

wherein: R¹ is hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R² is alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R³ isindependently hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.
 33. The compound of claim 32, or apharmaceutically acceptable salt thereof, wherein ring A is selected toprovide one of:


34. The compound of claim 32 or 33, or a pharmaceutically acceptablesalt thereof, wherein ring A is selected to provide one of:


35. The compound of any one of claims 32-34, or a pharmaceuticallyacceptable salt thereof, wherein: R¹⁶ is hydrogen or —W—X, wherein W is—O—, —S— or —NH—, and X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; R¹ is hydrogen, alkyl, alkylsulfonyl,alkylsulfinyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and R² is alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 36. The compound ofany one of claims 32-35, or a pharmaceutically acceptable salt thereof,wherein: R¹⁶ is —W—X, wherein W is —O— and X is alkyl aryl, cycloalkyl,or cycloalkylalkyl; R¹ is hydrogen or alkyl; and R² is alkyl.
 37. Thecompound of any one of claims 32-36, or a pharmaceutically acceptablesalt thereof, wherein R¹⁶ is:


38. The compound of any one of claims 32-37, or a pharmaceuticallyacceptable salt thereof, wherein R¹⁶ is:


39. The compound of claim 30, or a pharmaceutically acceptable saltthereof, wherein ring B is selected to provide one of:

and wherein: R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and each R³ is independently hydrogen, halogen, alkyl,alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.
 40. The compound of claim 39, or apharmaceutically acceptable salt thereof, wherein ring B is selected toprovide one of the following:


41. The compound of claim 39 or 40, or a pharmaceutically acceptablesalt thereof, wherein ring B is selected to provide one of thefollowing:


42. The compound of any one of claims 39-41, or a pharmaceuticallyacceptable salt thereof, wherein: R¹³ is —Y—Z, in which Y is a bond or—CH₂—, Z is —SO₂R^(b), —N(R^(a))SO₂R^(b), or —SO₂N(R^(a))₂, each R^(a)is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl.
 43. The compound of any one of claims 39-42, or apharmaceutically acceptable salt thereof, wherein: R¹³ is —Y—Z, in whichY is a bond or —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), each R^(a) isindependently hydrogen or alkyl, and R^(b) is alkyl; R¹ is alkyl,cycloalkylalkyl, or aralkyl; and R³ is hydrogen, halogen, alkyl, oralkoxy.
 44. The compound of claim 31, or a pharmaceutically acceptablesalt thereof, wherein ring C is selected to provide one of thefollowing:

and wherein: R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl.
 45. The compound of claim 43, or a pharmaceuticallyacceptable salt thereof, wherein ring C is selected to provide one ofthe following:


46. The compound of claim 44 and 45, or a pharmaceutically acceptablesalt thereof, wherein ring C is:


47. The compound of any one of claims 44-46, or a pharmaceuticallyacceptable salt thereof, wherein: R¹³ is —Y—Z, in which Y is s a bond or—CH₂—, Z is —SO₂R^(b), —N(R^(a))SO₂R^(b) or —SO₂N(R^(a))₂, each R^(a) isindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R³ is hydrogen, halogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl.
 48. The compound of any one of claims 44-47, or apharmaceutically acceptable salt thereof, wherein: R¹³ is —Y—Z, in whichY is a bond or —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), in which eachR^(a) is independently hydrogen or alkyl, and R^(b) is alkyl; R¹ isalkyl; and R³ is alkyl, cycloalkyl, or aryl.
 49. The compound of claim4, or a pharmaceutically acceptable salt thereof, wherein the compoundof Formula IV is of Formula IVa:


50. The compound of claim 49, or a pharmaceutically acceptable saltthereof, wherein R¹³ is —Y—Z, in which Y is s a bond or —CH₂—, Z is—SO₂R^(b), —N(R^(a))SO₂R^(b), or —SO₂N(R^(a))₂, each R^(a) isindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R¹⁶ is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.
 51. The compound of claims 49 or 50, ora pharmaceutically acceptable salt thereof, wherein R¹³ is —Y—Z, inwhich Y is a bond or —CH₂—, Z is —SO₂R^(b) or —N(R^(a))SO₂R^(b), eachR^(a) is independently hydrogen or alkyl, and R^(b) is alkyl; and R¹⁶ isalkyl or cycloalkylalkyl.
 52. A compound of Formula Va:

or a pharmaceutically acceptable salt thereof, wherein, Ring A is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S or N atom, or an optionally substituted 5- or 6-memberedheterocyclyl ring containing at least one S or N atom; X2 is N or C—R¹²,in which R¹² is hydrogen, halogen, alkyl, or alkoxy; X5 is N or C—R¹⁵,in which R¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy; and X6 is N orC—R¹⁶, in which R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond,—O—, —S—, or —NH—, and X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.
 53. A compound of Formula Vb:

or a pharmaceutically acceptable salt thereof, wherein Ring B is anoptionally substituted 5- or 6-membered heteroaryl ring containing atleast one S or N atom, or an optionally substituted 5- or 6-memberedheterocyclyl ring containing at least one S or N atom; X2 is N or C—R¹²,in which R¹² is hydrogen, halogen, alkyl, or alkoxy; X3 is N or C—R¹³,in which R¹³ is —Y—Z, wherein Y is selected from a bond, —CH₂—, or—CH(C₁-C₄ alkyl)-, and Z is selected from —SO₂R^(b), —N(R^(a))SO₂R^(b),—SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂, —CON(R^(a))₂, —N(R^(a))CO₂R^(a),—N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a), —OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂,or —N(R^(a))SO₃R^(b), each R^(a) is independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R^(b) is selectedfrom alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and X6 is N or C—R¹⁶,in which R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,—S—, or —NH—, and X is selected from alkyl, alkynyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 54. A compound ofFormula Vc, or a pharmaceutically acceptable salt thereof,

wherein: Ring C is an optionally substituted 5- or 6-membered heteroarylring containing at least one O, S or N atom; X2 is N or C—R¹², in whichR¹² is hydrogen, halogen, alkyl, or alkoxy; X3 is N or C—R¹³, in whichR¹³ is —Y—Z, in which Y is a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-, and Z is—SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,—CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),—OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein eachR^(a) is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is selected from alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; and X4 is N or C—R¹⁴, in which R¹⁴ ishydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy.
 55. A compound ofFormula Vd, or a pharmaceutically acceptable salt thereof,

wherein each R¹² is independently hydrogen, halogen, alkyl, or alkoxy;R¹³ is —Y—Z, in which Y is a bond, —CH₂— or —CH(C₁-C₄ alkyl)-, and Z is—SO₂R^(b), —N(R^(a))SO₂R^(b), —SO₂N(R^(a))₂, —N(R^(a))SO₂N(R^(a))₂,—CON(R^(a))₂, —N(R^(a))CO₂R^(a), —N(R^(a))CON(R^(a))₂, —N(R^(a))COR^(a),—OC(O)N(R^(a))₂, —OSO₂N(R^(a))₂, or —N(R^(a))SO₃R^(b), wherein eachR^(a) is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and R^(b) is alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and R¹⁶ is selected from alkyl, alkynyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 56. A compound ofFormula Ve:

or a pharmaceutically acceptable salt thereof, wherein J is N or C—R¹²,in which R¹² is hydrogen, halogen, alkyl, or alkoxy; R¹³ is —Y—Z, inwhich Y is a bond, —CH₂—, or —CH(C₁-C₄alkyl)-, and Z is —SO₂R²¹,—N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂,—N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂,—OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, in which each R²¹ is independentlyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each R²²is independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; K is N or C—R¹⁴, in which R¹⁴ ishydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; Q is N or C—R¹⁵,in which R¹⁵ is hydrogen, halogen, —CN, alkyl, alkoxy, aryloxy,aralkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heteroarylalkyloxy, oralkynyloxy; and R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein Wis a bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 57. Acompound of Formula VI, or a pharmaceutically acceptable salt thereof,in which Formula VI is:

wherein n is 0 to 4; m is 0 or 1; R^(A) is a halogen, C1-3 alkyl, orC1-3 alkoxy; J is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl,or alkoxy; R¹³ is —Y—Z, in which Y is a bond, —CH₂—, or—CH(C₁-C₄alkyl)-, and Z is —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,—N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,—N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹,wherein each R²¹ is independently alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and each R²² is independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl. K is N or C—R¹⁴,wherein R¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; Qis N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl, alkoxy,aryloxy, aralkyloxy, cycloalkylalkyloxy, heterocyclyloxy,heteroarylalkyloxy, or alkynyloxy; and R¹⁶ is hydrogen, halogen,—N(H)COX, or —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X isselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl,or heteroarylalkyl.
 58. A composition comprising at least one of thefollowing compounds:N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]ethanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]indazol-4-yl]ethanesulfonamide;N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide;N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]methanesulfonamide;N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1-benzofuran-5-yl]ethanesulfonamide;N-[7-(2-methyl-1-oxoisoquinolin-4-yl)-2-phenyl-1-benzofuran-5-yl]methanesulfonamide;4-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin1-one;4-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one;4-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one;N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol-4-yl]methanesulfonamide;N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indol-4-yl]methanesulfonamide;N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydroindol-4-yl]methanesulfonamide;N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-2,3-dihydroindol-4-yl]methanesulfonamide;4-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one;2-methyl-4-(5-methylsulfonyl-2-phenyl-1-benzofuran-7-yl)isoquinolin-1-one;N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzotriazol-4-yl]ethanesulfonamideN-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]benzotriazol-4-yl]ethanesulfonamide;4-[6-(cyclopropylmethoxy)-1-methyl-3-methylsulfonylindazol-5-yl]-2-methylisoquinolin-1-one;4-[6-(cyclopropylmethoxy)-3-ethylsulfonyl-1methylindazol-5-yl]-2-methylisoquinolin-1-one;N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]methanesulfonamideN-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]methanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]ethanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide;N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide;N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indazol-4-yl]ethanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4-yl]methanesulfonamide;N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4-yl]methanesulfonamide;4-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-2-methylisoquinolin1 one;N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethoxybenzimidazol-4-yl]methanesulfonamide;N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4-yl]methanesulfonamide;N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1-benzofuran-5-yl]methanesulfonamide;N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide;4-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one;N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1-benzofuran-5-yl]ethanesulfonamide;or a pharmaceutical salt of any of these.
 59. A pharmaceuticalcomposition comprising the compound as characterized in any one of thepreceding claims.
 60. The pharmaceutical composition of claim 59,wherein the compound is4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one,or a pharmaceutically acceptable salt thereof; or4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 61. An oral dosage formcomprising the pharmaceutical composition of claim
 59. 62. A medicamentcomprising the pharmaceutical composition of claim 59 for use in thetreatment of cancer or other neoplastic disease.
 63. Use of a compoundor pharmaceutical composition of any one of the preceding claims forpreparation of a medicament for treating cancer or other neoplasticdisease.
 64. A method of modulating the epigenetic status of a cellcomprising contacting the cell with the compound of any one of claims1-58.
 64. A method for inhibiting a histone demethylase enzymecomprising contacting a histone demethylase enzyme with the compound ofany one of claims 1-58.
 65. A method for treating cancer or neoplasticdisease in a subject in need of such treatment comprising administeringto the subject the pharmaceutical composition of claim 59.